Jill Williams, MD

UMDNJ-Robert Wood Johnson Medical School
Alcohol Medical Scholars Program

Revised March 26, 2007


Assessment and Pharmacological Treatment of Tobacco Dependence

< Slide 1>


I. Introduction

            A. Tobacco use is common and has many devastating effects < Slide 2>

1.  ~70 million cigarette smokers in US

2.  Number one preventable cause of morbidity/ mortality in US

3. > 500,000 premature deaths/year from tobacco[1]

4. 50,000 deaths (in nonsmokers) from environmental tobacco smoke[2]

5. Tobacco and nicotine differ - Tobacco is the harmful part of smoking, not nicotine.  It’s the smoke that kills


            B. Many smokers want to quit and treatments improve outcomes < Slide 2>

            1. 41% of smokers try to quit each year

2.  Assessment guides treatment

3.  Brief advice from a physician increases quitting

4.  Treatments double success rates


            C. This lecture will cover  < Slide 3>

1.      Epidemiology and consequences

2.      Nicotine pharmacology

3.      Assessment

4.      Pharmacological treatments



II. Epidemiology and consequences of tobacco use < Slide 4>

A. Epidemiology

                        1. >1 billion tobacco users worldwide

                                    a. ↑ in developing regions (China, India, Africa, S. America)

                                    b. Stable or ↓ in developed nations

2. ~23% of US population smokes cigarettes < Slide 5>

            a.  3% of physicians[3]

            b. 70% with mental illness or SUD [4],[5]

            c. Smoking prevalence ↓ 1960s, but stable~ last 15 years

                        3. Tobacco forms

a. Cigarettes > 95% of all tobacco use

                                    b. Cigar smoking

                                                1). Non-daily use patterns

2). ~5% prevalence; increased > 50 percent since 1990s

3). ↑ in youth, women, minority groups

                                    c. Chewing tobacco

                                                1). Loose leaf or snuff

2) 3.5% prevalence (Men use 7x > women) [6]

                        4.  Prevalence ↑ in lower SES

5. Males > females[7]; women ↑since 1950s (lung cancer deaths > breast cancer deaths since 1987) [8]   < Slide 6>

6.  Recent ↑ in youth smoking (“Pediatric epidemic”)  < Slide 7>

a.   Initiation during grades 6-9 (ages 11-15).

b.      90% of all smokers start before age 18

c.       If begin < 16, 1.6x be dependent [9]

d.      5 million US smokers aged 12-17 years


B. Morbidity and mortality < Slide 8>

1. Half of smokers die from a tobacco-caused disease (~ 1 in 5 US deaths)

2. Cancer

a. ~90% of lung cancers from smoking[10]

1). #1 cause of cancer deaths in US

2). 15% 5-year survival rate

b. Other types   < Slide 9>

{SOURCE: 2004 Surgeon General Report on the Health Consequences of Smoking}

1). Oral cancers (lip, tongue, mouth, and larynx)

2). Esophagus, cervix, bladder, pancreas, and kidney

3. Causes ~100% COPD

4.      2x ↑ death from stroke/ coronary heart disease


C. Other consequences

1. Costs > $100 billion annually

a. $50 billion in medical costs

b. $50 billion lost productivity

                        2.  Primary cause of fatal house fires


III. Assessment and treatment

A. Components of tobacco smoke < Slide 10>

            1. Smoke > than 4000 chemicals

                        a. Carbon monoxide

b. Other toxins

1). Hydrogen cyanide

2). Formaldehyde

3). Ammonia

2. Smoke > 60 carcinogens (benzene, cadmium, nitrosamines, polycyclic aromatic hydrocarbons (PAH))

3. Environmental Tobacco Smoke (ETS) < Slide 11>

a. Smoke from cigarettes of others

b. Class1A carcinogen, same class as asbestos

            c. 50,000 additional deaths/ year in non-smokers (3000 lung cancer)

4.      Nicotine pharmacology depends on delivery route < Slide 13>

a.        Short half-life (2 hours)

b.      Best absorption when smoked[11]

            1). Cigarettes (smoking) “perfect” drug delivery device

            2)  Reaches brain in 10 sec[12]

            3). Most reinforcing form

            c. Binds to nicotinic cholinergic receptors

            d. Arterial levels 6-10x higher than venous

            e.  Metabolized to cotinine in liver

5. Nicotine researched for possible therapeutic effect < Slide 15>

            a. Ulcerative colitis[13]

            b. Alzheimer's disease

            c.  Parkinson's disease

            d. Tourette's syndrome[14]

            e. Attention deficit disorder[15]

            f.  Schizophrenia[16]

6. Nicotine safety < Slide 16>

            a.  Not a carcinogen

            b.  Not a risk factor for cardiovascular events, even in people with         cardiovascular disease [17], [18], [19]

            c. Risk-benefit ratio supports of using nicotine products over using         tobacco[20]

            d. Smokers misinformed re: safety/efficacy of nicotine[21]


B. Assessment guides treatment

1. DSM IV criteria [22] < Slide 18>

            a.  Nicotine dependence

1). DSM not list abuse: Clinically significant psychosocial problems rare

                        2). ≥ 90% smokers meet dependence criteria[23]

                        3). 3 or more of 7 DSM dependence criteria

a). Persistent desire or unsuccessful efforts to cut down or control use

b) Activities given up or reduced

c). Use despite a physical or psychological problem

d). Tolerance

e). Withdrawal

b.  Nicotine withdrawal < Slide 19>

                        1) Symptoms

                                                      a). Dysphoric or depressed mood

b). Insomnia

c). Irritability, frustration or anger

d). Anxiety

e). Difficulty concentrating

f). Restlessness

g). Decreased heart rate

h). Increased appetite or weight gain

                        2). Duration

a). Most severe 1-3 days after quitting

b). Can last 4 weeks

2. Heaviness of smoking index = measure dependence severity [24]  < Slide 20>

a.  Number of cigarettes per day (cpd) smoked

                        b.  Time to first cigarette (TTFC)

                                    1). Smokers awaken in nicotine withdrawal

2). Smoking ≤ 30 minutes of awakening = moderate dependence

3). Smoking ≤ 5 minutes of awakening = severe dependence


C. Motivation to quit < Slide 21>

1. 70% of smokers want to quit

2. Few quit successfully without treatment

a. 33% of self-quitters remain abstinent for 2 days

b. < 5% successful


D. Provider’s role in treatment < Slide 22>

{SOURCE: PHS Guidelines, Treating Tobacco Use and Dependence: Clinical Practice Guidelines,              US Dept Health and Human services}

1.      Use 5As for primary care settings (ask, advise, assess, assist, and arrange)

                        a.  Ask—identify all tobacco users at every visit

                        b. Advise—urge users to quit

                        c. Assess—determine willingness to quit

                        d. Assist—aid in quitting

                        e. Arrange—follow-up

2.      Brief physician advice quitting [25]

3.      More physician counseling is better

a. 10% quit rates with < 3 minutes

b. 20% quit rates >10 minutes


E. Treatments ↑ long-term abstinence

1.      Tobacco dependence = chronic condition

            a. < 25% quit successfully on their first attempt

            b.  Usually 8 quit attempts before successful[26]

2. Pharmacotherapy a first line treatment [27]

            a. Doubles success

b. Recommended for all who try to quit, unless contraindications

                        c. Works even without psychosocial treatments [28]

d. Best outcomes: meds +  psychosocial[29]


IV. Rationale for pharmacotherapy [30] < Slide 24>

            A.  ↓ or eliminate withdrawal

            B.  ↓ reinforcement by nicotine [31],[32]

            C.  ↓ weight gain when quitting

            D.  Unlearn smoking behaviors

            E.  Manage negative mood

F. Cost-effective [33],[34]

1. Treatment cost  per smoker $165 17

2. More cost-effective than mammography, anti-HTN drugs


V. First-line/ FDA approved pharmacological treatments          

            A.  Poor absorption from nicotine replacement medication (NRT)[35],[36]  < Slide 26>

                        1.  Nicotine absorption is pH dependent

                        2.  Lower dose delivered

                        3.  Less reinforcing than smoking [37]

                        4.  Poorly absorbed orally

                        5.  Poor compliance and under dosing  common [38]

6.  Relative contraindications to NRT 11 < Slide 27>

a. Few unable to take nicotine

b. With caution in selected populations

1). Recent MI

2). Uses < 10 cigarettes per day

3). Pregnant/breastfeeding

4). Adolescents (Not FDA approved)

7.       Side effects NRT

a. Usually mild

b. Local irritant at site of use

c. Systemic side effects less common


2). Nausea

3). Headache

8. Start NRT on the quit date (QD)


B.  Nicotine patch[39]      < Slide 28>

1.      Slow onset of action

a.       30 min to onset

b.      6 h to peak

2.      Continuous delivery

a.       24 or 16 hour dosing

b.      Night wearing relieves morning craving but disturbs sleep

c.       Given with gradual taper

3.      Passive dosing

a.       Easy to use

b.      Best compliance44

c.       No response to acute craving

4.      Side effects

a.       Skin

1). Itching, tingling at patch site

2). True rash rare

b.      Sleep disturbance, abnormal dreaming

5.      Availability and cost

a.       OTC

b.      $50 for 2 week supply


C.     Nicotine gum < Slide 29>

1.      Buccal absorption

a.   20-30  min onset of action

b.  Reduced with acidic beverages (soda, coffee)

c.   Bite and park method improves absorption and reduces side effects

2.      Side effects

a.       Mild- peppery taste

b.      Throat irritation

c.       Dyspepsia

d.      Jaw soreness

3.      Dosing

a.       1 piece an hour

b.      ↑ for cravings (up to 24 pieces/ day)

c.       6 weeks than taper

d.      Longer more helpful

e.       Dose: 2mg < 25 cpd; 4 mg> 25 cpd

4.      Limitations

a.       TMJ

b.      Dental problems, edentulous

5.      Availability and cost

a.       OTC

b.      $50 for 2 week supply

c.       Generics available ($25-$35)


D.     Nicotine lozenge  < Slide 30>

1.      Buccal absorption (similar to gum, more discreet)

a.       Reduced with acidic beverages

b.      Dissolve; don’t chew (15 min)

2.      Side effects

a.       Mild

b.      Throat irritation

3.      Dosing

a.       1 piece an hour, for cravings

b.      Max 20 per day

c.       6 weeks than taper

d.      Dose based on TTFC instead of number of cpd

e.       Dose: 2mg  if > 30 mins TTFC ; 4 mg< 30 mins TTFC [40]

4.      Availability and cost

a.       OTC

b.      $80 for 2 week supply

c.       No generics

5.      Limitations: none


E.      Nicotine inhaler  < Slide 31>

1.      Buccal absorption

a.       Oral puffer; inhaler misnomer

b.      Reduced with acidic beverages

c.       Hand to mouth activity helpful for some

2.      Side effects

a.       Mild

b.      Throat irritation

c.       Cough

3.      Dosing

a.       6-16 cartridges per day

b.      Puff for 20 min

4.      Limitations - frequent and continuous puffing  (80 puffs =1 cigarette)

5.      Availability and cost

               a.   Prescription

b.   Packaged #42 or #168 cartridges (approx $1/cartridge)

                        c.   Not covered by all insurance


F.      Nicotine nasal spray  < Slide 32>

1.      Rapid delivery though nasal mucosa

a.       Onset  in  minutes[41]

b.      Modest peak in 10 minutes

2.      Side effects[42]

a.       Moderate- can lead to discontinuation

b.      Sneezing

c.       Runny nose, watery eyes

d.      Burning in nasal mucosa

e.       Risk for bronchospasm (h/o asthma)

f.        Tachyphylaxis- remit with continued use

3.      Dosing

a.       One spray each nostril = 1 dose (2 sprays)

b.      Minimum  8 doses/day

c.       1-2 doses/ hr

d.      40 doses/ day max

4.      Limitations

a.       Side effects

b.      High early discontinuation

c.       Dependence in 30% + using >6 months [43], [44]

5.      Availability and cost

a.   Prescription

b.   Packaged as 4 -10mL bottles

c.   Cost: $5/day; $45/ bottle

d.   Not covered by all insurance


G.     Bupropion < Slide 33>

1.      Pharmacology

a.       Zyban SR= Wellbutrin SR

b.      Accidental discovery as smoking aid

c.       Activating, non-sedating antidepressant

d.      Effects on DA and NE

e.       Effects as nicotinic receptor antagonist [45],[46]

2.      Side effects

a.       Mild to moderate

b.      Headache

c.       Anxiety, agitation

d.      Dry mouth

e.       Insomnia

3.      Dosing

a.       150 mg x 3-7 days, then ↑ up to 300mg daily

b.      Start 2 weeks before quit date

c.       7-12 weeks maintenance up to 6 months

d.      300 mg dose associated with least weight gain (1-2 lbs at 6 mos) [47]

4.      Limitations/ contraindications

a.       Seizure

b.      Eating disorder

c.       Current use of Wellbutrin or MAO inhibitors

5.      Availability and cost

a.       Prescription

b.      Reimbursable as Wellbutrin, often not as Zyban

c.       Cost $3 per day


H.     Efficacy < Slide 34>

1.      Nicotine replacement

                                                                               a.      Doubles the likelihood of success in stopping smoking as compared with placebo or no NRT 23

                                                                              b.      Meta-analysis of 110 randomized trials, 35,000 patients.  Odds ratio of 6 months abstinence compared to placebo 25

1). Overall 1.74

      2). Gum 1.66

      3). Patch 1.74

4). Inhaler 2.08

5). Nasal spray 2.27

6). Lozenge 2.08

                                                                               c.      Success rates 25-30% at 12 weeks

                                                                              d.      No differences in outcomes in a randomized trial of 4 types of NRT (gum= patch= nasal spray= inhaler) [48]

2.      Bupropion 

                                                                               a.      Efficacy comparable to NRT [49] or ? slightly higher [50]

                                                                              b.      Efficacy independent of antidepressant properties [51],[52]

3.      Patient preference, cost, tolerability

4.      Combination therapy may improve outcomes

                                                                               a.      Nicotine combinations

1).  Sustained plus immediate acting for craving relief[53]

2).  Improves abstinence outcomes [54]

3). Greater withdrawal relief [55]

                                                                              b.      Nicotine plus bupropion

   1). No medication interactions/ precautions

2). Commonly given clinically

3). Efficacy unknown, not well studied


I.        Varenicline < Slide 35>

1.      Partial nicotine agonist [56]

                                                                               a.       Eliminate reward from smoking

                                                                              b.       Prevent withdrawal symptoms

                                                                               c.       Not addicting

                           2. 1mg BID dose superior to placebo or bupropion in 12 week trials[57],[58]

                           3.  Additional 12 weeks prevented relapse in continuation study[59]

                           4.  Most common side effects

                                       a.   Nausea

                                       b.   Headache

                                       c.   Insomnia

                                       d.   Abnormal dreams


VI. Conclusions < Slide 36>

1.  All practitioners should treat tobacco

2.  Pharmacotherapy doubles the success rates in making a quit attempt and should be used in all smokers trying to quit

            3.  Six FDA approved treatments are effective and well tolerated


[1] Cigarette smoking-attributable morbidity--United States, 2000.  Morbidity and mortality weekly report: MMWR 2003; 52:842-4


[2] Centers for Disease Control and Prevention (CDC). State-specific prevalence of current cigarette smoking among adults and the proportion of adults who work in a smoke-free environment--United States, 1999.
MMWR 2000;49:978-82.


[3] Nelson DE, Giovino GA, Emont SL, Brackbill R, Cameron LL, Peddicord J, Mowery PD: Trends in cigarette smoking among US physicians and nurses.  JAMA 1994; 271:1273-1275


[4] Lasser K, Wesley BJ, Woolhandler S, Himmestein DU, McCormick D, Bor DH: Smoking and mental illness: a population-based prevalence study.  JAMA 2000; 284:2606-2610


[5] Hughes JR, Hatsukami DK,  Mitchell JE, Dahlgren LA:  Prevalence of smoking among psychiatric outpatients.  Am J Psychiatry 1986; 143:993-997


[6] Substance Abuse and Mental Health Services Administration. Results from the 2002 National Survey on Drug Use and Health. Detailed Tables. Rockville, MD: Substance Abuse and Mental Health Services Administration, Office of Applied Studies; 2003


[7] State-specific prevalence of current cigarette smoking among adults—United States, 2003. MMWR 2004; 53:1035-1037


[8] MMWR.  Mortality Trends for Selected Smoking-Related Cancers and Breast Cancer -- United States, 1950-1990 Morbid Mort Wkly Rep. November 12, 1993; 42;863-866


[9] Breslau N, Fenn N, Peterson EL: Early smoking initiation and nicotine dependence in a cohort of young adults. Drug Alcohol Depend 1993; 33:129-37


[10]The Health Consequences of Smoking: A Report of the Surgeon General. Washington, DC: National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2004


[11] Russell MAH, Jarvis MJ, Feyerabend C, et al.  Nasal nicotine solution: a potential aid to giving up smoking? BMJ 1983; 286: 683-4


[12] Henningfield JE, Stapelton JM, Benowitz NL, Gryson RF, London ED: Higher levels of nicotine in arterial than in venous blood after cigarette smoking. Drug  Alcohol Depend 1993; 33:23-29.


[13] McGrath J, McDonald JW, Macdonald JK. Transdermal nicotine for induction of remission in ulcerative colitis.
Cochrane Database Syst Rev. 2004; 4: CD004722. Review


[14] Silver AA, Shytle RD, Philipp MK, Wilkinson BJ, McConville B, Sanberg PR .Transdermal nicotine and haloperidol in Tourette's disorder: a double-blind placebo-controlled study. J Clin Psychiatry 2001; 62:707-14


[15] Conners CK, Levin ED, Sparrow E, Hinton S, Ernhardt D,  Meck WH, Rose JE, March J: Nicotine and attention in adult ADHD. Psychopharmacol Bull 1996; 32:67-73.


[16] Adler LE, Hoffer LD, Wiser A,  Freedman R: Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 1993; 150:1856-1861


[17]Benowitz NL, Gourlay SG: Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy.  J Am Coll Cardiology 1997; 29:1422-1431


[18] Joseph AM, Norman SM, Ferry LH: The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease.  N Engl J Med 1996; 335:1792-1798


[19] Murray RP, Bailey WC, Daniels K, Bjornson WM, Kurnow K, Connett JE, Nides MA, Kiley JP:  Safety of nicotine polacrilex gum used by 3094 participants in the lung health Study.  Chest 1996; 109:438-445


[20] Heishman SJ.   Nicotine: Pharmacology and addiction. Ther Drug Monit 1999; 20: 223-238


[21] Bansal MA, Cummings KM, Hyland A, Giovino GA: Stop-smoking medications: who uses them, who misuses them, and who is misinformed about them?  Nicotine Tob Res 2004; 6 Suppl 3:S303-10


[22] American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision: DSM-IV-TR, Washington, DC: American Psychiatric Association, 2000


[23] Rigotti NA:  Treatment of tobacco use and dependence. N Engl J Med 2002; 346:506–512


[24] Heatherton TF, Kozolwski L, Frecker RC, Rickert W, Robinson J:  Measuring the heaviness of smoking: using self-reported time to the first cigarette of the day and number of cigarettes smoked per day. Br J Addiction 1989; 84: 791-799


[25] Fiore MC, Bailey WC, Cohen SJ, Dorfman SF, Goldstein MG, Gritz ER, Heyman RB, Jaen CR, Kottke TE, Lando HA, Mecklenburg RE, Mullen PD, Nett LM, Robinson L, Stitzer ML, Tommasello AC, Villejo L, Wewers ME: Treating Tobacco Use and Dependence: Clinical Practice Guidelines.  Rockville, MD: U.S.  Department of Health and Human Services. Public Health Service. 2000


[26] Schroeder SA: What to do with a patient who smokes. JAMA 2005; 294:482-7


[27] Silagy C, Lancaster T, Stead L, Mant D, Fowler G. Nicotine replacement therapy for smoking cessation. Cochrane Database Systematic Review 2004; (3):CD000146. Review


[28] Henningfield JE, Fant RV, Buchhalter AR, Stitzer ML:  Pharmacotherapy for nicotine dependence.  CA Cancer J Clin 2005; 55:281-99


[29] Hughes JR:  Combining behavioral therapy and pharmacotherapy for smoking cessation: an update. NIDA Res Monogram 1995; 150:92-109


[30] Foulds J, Burke M, Steinberg M, Williams JM and Ziedonis DM:  Advances in Pharmacotherapy for Tobacco Dependence.  Expert Opin Emerg Drugs 2004; 9:39-51


[31] Rose JE, Corrigall WA:  Nicotine self-administration in animals and humans: similarities and differences. Psychopharmacology (Berl) 1997; 130:28-40


[32] Benowitz NL, Zevin S, Jacob P:  Suppression of nicotine intake during ad libitum cigarette smoking by high-dose transdermal nicotine.  J Pharmacol Exp Ther 1998; 287:958-962


[33] Song F, Raftery J, Aveyard P, Hyde C, Barton P, Woolacott N:  Cost-effectiveness of pharmacological interventions for smoking cessation: a literature review and a decision analytic analysis. Medical Decision Making  2002; 22(5 Suppl): S26-37


[34] Woolacott NF, Jones L, Forbes CA, Mather LC, Sowden AJ, Song FJ, Raftery JP, Aveyard PN, Hyde CJ, Barton PM:  The clinical effectiveness and cost-effectiveness of bupropion and nicotine replacement therapy for smoking cessation: a systematic review and economic evaluation.  Health Technology Assessment 2002; 6:1-245

[35] Benowitz NL:  The human pharmacology of nicotine. Res Adv Alcohol Drug Probl 1986; 9:1-51.


[36] Perkins KA, Lerman C, Keenan J, Fonte C, Coddington S:  Rate of nicotine onset from nicotine replacement therapy and acute responses in smokers.  Nicotine Tob Res 2004; 6:501-507


[37] Hughes JR:  Dependence potential and abuse liability of nicotine replacement therapies.  Biomed and Pharmacotherapy 1989; 43:11-17


[38] Hughes JR, Goldstein MG, Hurt RD and Shiffman S:  Recent advances in pharmacotherapy of smoking.  JAMA 1999; 281:72-76.


[39] Palmer KJ, Buckley MM, Faulds D:  Transdermal nicotine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy as an aid to smoking cessation.  Drugs 1992;44:498-529


[40] Shiffman S, Dresler CM, Hajek P, Gilburt SJ, Targett DA, Strahs KR:  Efficacy of a nicotine lozenge for smoking cessation. Arch  Internal Medicine 2002; 162:1267-76


[41] Sutherland G, Russell MAH, Stapleton J, Feyerabend C, Ferno O:  Nasal nicotine spray: a rapid nicotine delivery system. Psychopharmacology 1992; 108:512-518


[42] Hurt RD, Dale LC, Croghan GA, Croghan IT, Gomez-Dahl LC, Offord KP:  Nicotine nasal spray for smoking cessation: pattern of use, side effects, relief of withdrawal symptoms, and cotinine levels.  Mayo Clin Proc 1998;73:118-25


[43] West R, Hajek P, Foulds J, Nilsson F, May S, Meadows A:  A comparison of the abuse liability and dependence potential of nicotine patch, gum, spray and inhaler. Psychopharmacology 2000; 149:198-202


[44] Schuh KJ, Schuh LM, Henningfield JE, Stitzer ML:  Nicotine nasal spray and vapor inhaler: abuse liability assessment.  Psychopharmacology 1997;130:352-361


[45] Fryer JD, Lukas RJ.  Noncompetitive functional inhibition at diverse, human nicotinic acetylcholine receptor subtypes by bupropion, phencyclidine, and ibogaine.  J Pharmacol Exp Ther 1999; 288:88-92


[46] Slemmer JE, Martin BR, Damaj MI. Bupropion is a nicotinic antagonist.  J Pharmacol Exp Ther 2000; 295:321-7.


[47] Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC, Khayrallah MA, Schroeder DR, Glover PN, Sullivan CR, Croghan IT, Sullivan PM:  A comparison of sustained-release bupropion and placebo for smoking cessation.  N Engl J Med 1997; 337:1195-202.


[48] Hajek P, West R, Foulds J, Nilsson F, Burrows S, Meadow A:  Randomized comparative trial of nicotine polacrilex, a transdermal patch, nasal spray and an inhaler.  Arch Intern Med 1999;159:2033-2038


[49] Hurt RD, Sachs DP, Glover ED, Offord KP, Johnston JA, Dale LC, Khayrallah MA, Schroeder DR, Glover PN, Sullivan CR, Croghan IT, Sullivan PM: A comparison of sustained-release bupropion and placebo for smoking cessation.  N Engl J Med 1997; 337:1195-202.


[50] Jorenby DE, Leischow SJ, Nides MA, Rennard SI, Johnston JA, Hughes AR, Smith SS, Muramoto ML, Daughton DM, Doan K, Fiore MC, Baker TB:  A controlled trial of sustained-release bupropion, a nicotine patch, or both for smoking cessation.  N Engl J Med 1999; 340:685-691


[51] Hayford KE, Patten CA, Rummans TA, Schroeder DR, Offord KP, Croghan IT, Glover ED, Sachs DPL, Hurt RD:  Efficacy of bupropion for smoking cessation in smokers with a former history of major depression or alcoholism.  Br J Psychiatry 1999; 174:173-178


[52] Cox LS, Patten CA, Niaura RS, Decker PA, Rigotti N, Sachs DP, Buist AS, Hurt RD: Efficacy of bupropion for relapse prevention in smokers with and without a past history of major depression.  J Gen Intern Med 2004; 19:828-34.


[53] Hurt RD. Treating tobacco dependence in a medical setting—best practices. In: Isaacs SL, Simon JA, Schroeder SA, eds.  VA in the Vanguard: Building on Success in Smoking Cessation. Proceedings of Conference, San Francisco, September 21, 2004. 


[54] Kornitzer M, Boutsen M, Dramaix M, Thijs J, Gustavsson G: Combined use of nicotine patch and gum in smoking cessation: a placebo-controlled clinical trial.  Prev Med 1995; 24:41-7


[55]  Fagerstrom KO, Schneider NG, Lunell E: Effectiveness of nicotine patch and nicotine gum as individual versus combined treatments for tobacco withdrawal symptoms. Psychopharmacology (Berl) 1993;111:271-7.


[56] Coe JW, Brooks PR, Vetelino MG, Wirtz MC,  O’Neill BT, Sands SB, Lebel LA, Fox CB, Shrikhande A, Tingley FD, Davis TI, Rollema H,  Lu Y, Schaeffer E, Holland JP, Mansbach RS, Schulz DW: Varenicline (CP-526, 555): A novel, potent, and selective nicotinic receptor partial agonist for the treatment of smoking cessation: Rationale, discovery, and mode of action.  Presented at the 11th Annual Meeting of the Society for Research on Nicotine and Tobacco, Prague, March 2005.


[57] Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB, Watsky EJ, Gong J, Williams KE, Reeves KR; Varenicline Phase 3 Study Group. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial.
JAMA. 2006 Jul 5;296(1):47-55.


[58] Jorenby DE, Hays JT, Rigotti NA, Azoulay S, Watsky EJ, Williams KE, Billing CB, Gong J, Reeves KR; Varenicline Phase 3 Study Group. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial.
JAMA. 2006 Jul 5;296(1):56-63.


[59] Tonstad S, Tonnesen P, Hajek P, Williams KE, Billing CB, Reeves KR; Varenicline Phase 3 Study Group. Effect of maintenance therapy with varenicline on smoking cessation: a randomized controlled trial.
JAMA. 2006 Jul 5;296(1):64-71.