Smoking Cessation Pharmacotherapy Melodie Merzier-Michel PGY-1 Pharmacy Resident Memorial Regional Hospital www.fshp.org Objectives Discuss the prevalence of tobacco use in the United States (U.S.) Describe the health risks associated with smoking Describe the health benefits of smoking cessation Define smoking cessation Recognize the 5 A s to promote smoking cessation Highlight the role of nicotine replacement therapy in smoking cessation Identify the use of other pharmacotherapies in smoking cessation 3 Disclosure The author of this presentation has nothing to disclose concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in the subject matter of this presentation. Prevalence of Tobacco Use In 2014, nearly 17 of every 100 U.S. adults 18 years or older (16.8%) or an estimated 40 million adults in the U.S., smoked cigarettes Each year there are 480,000 deaths attributed to smoking in the U.S Largest avoidable source of mortality 2 Economic Facts About U.S Tobacco Production and Use. Centers for Disease Control and Prevention. 4 1
Prevalence of Tobacco Use Second Hand Smoke Each day 4,000 minors, ages 12 to 17, smoke their first cigarette Approximately 1,200 children and adolescents become daily cigarette smokers More than 16 million Americans live with a smoking-related disease Smoke that has been exhaled, or breathed out, from burning tobacco products, such as: Cigarettes Cigars Pipes Economic Facts About U.S Tobacco Production and Use. Centers for Disease Control and Prevention. 5 Second Hand Smoke. Centers for Disease Control and Prevention. Updated 2015 7 Prevalence of Tobacco Use Second Hand Smoke Cigarettes account for greater than 90% of tobacco use Smokeless tobacco accounts for less than 5% Pipes and cigars account for less than 1% Accounts for approximately 2,500,000 deaths in nonsmokers Results in nearly 34,000 heart disease deaths each year Associated with more than 7,300 lung cancerrelated deaths each year Stead LF et al. Nicotine replacement therapy for smoking cessation. American Psychiatric Association, (2000). Diagnostic and Statistical Manual for Mental Disorders - V 6 Second Hand Smoke. Centers for Disease Control and Prevention. Updated 2015 8 2
Costs of Tobacco Use What s in a Cigarette? $96 billion dollars per year in direct medical expenses $156 billion dollars lost in work wages $193 billion dollars in annual health-related economic losses $300 billion dollars in total economic cost of smoking Economic Facts About U.S Tobacco Production and Use. Centers for Disease Control and Prevention. 9 Stead LF et al. Nicotine replacement therapy for smoking cessation http://resources0.news.com.au/images/2013/02/09/1226574/531308-nnd-whats-in-a-cigarette.jpg 11 Health Consequences of Smoking Health Consequences of Smoking Respiratory Effects Cardiovascular Effects Reproductive effects Cancer Smoking Other Diseases 10 Health Effects of Cigarette Smoking. Centers for Disease Control and Prevention.. 12 3
Health Consequences of Smoking Assessment Tools for Tobacco Dependence Fagerstrom Tolerance Questionnaire (FTQ) Fagerstrom Test for Nicotine Dependence (FTND) Diagnostic and Statistical Manual (DSM) Cigarette Dependence Scale (CDS) Nicotine Dependence Syndrome Scale (NDSS) Wisconsin Inventory of Smoking Dependence Motives (WISDM) https://upload.wikimedia.org/wikipedia/commons/9/92/risks_form_smoking-smoking_can_damage_every_part_of_the_body.png 13 Piper et al. (2006). Nicotine & Tobacco Research 15 Tobacco Dependence Nicotine Addiction Smoking within 30 minutes of awakening Smoking more than 20 cigarettes per day Awaking at night to smoke American Psychiatric Association, (2000). Diagnostic and Statistical Manual for Mental Disorders V 14 http://jerushaellis.ca/wp-content/uploads/2014/05/ellis_jerusha_smokingcessation_addiction.jpg 16 4
Nicotine Withdrawal Symptoms 5 A s Model for Treating Tobacco Use and Dependence Anxiety Craving Cognitive and attention deficits Depression Decreased heart rate Increased appetite or weight gain Irritability, frustration, anger Sleep disturbances ASK ADVISE ASSESS ASSIST ARRANGE American Psychiatric Association, (2000). Diagnostic and Statistical Manual for Mental Disorders V http://cf.chucklesnetwork.com/items/5/6/2/6/original/not-sure-if-hates-all-of-you-or-just-nicotine-withdrawal.jpg 17 19 Tobacco Dependence Methods for Enhancing Motivation to Quit The 5 R s 70 % of adult tobacco users report wanting to quit each year 44% of adult tobacco users report they try to quit each year Only 4-7% of tobacco users who attempt to quit are successful Relevance What s the most important reason for you to consider quitting? Risks What are the negative things you think about smoking? Rewards What are the benefits you may have if you stop smoking? Roadblocks What barriers do you have to quitting tobacco? Repetition Many people need 7 to 10 attempts before they are successful Lavinghouze et. al. Trends in Quit Attempts Among Cigarette Smokers. MMWR, October 16, 2015. Fiore et al. (2008). Treating Tobacco use and Dependence 18 20 5
Who Should Receive Treatment? All tobacco users trying to quit, except: Contraindication to pharmacotherapy Specific populations with insufficient evidence of effectiveness Adolescents Light smokers (<10 cigarettes a day) Pregnant women Smokeless tobacco users http://obamacarefacts.com/wp-content/uploads/2014/08/cdc-quit-smoking-facts-1024x643.jpg 21 Fiore et al. (2008). Treating Tobacco use and Dependence. 23 Considerations for Treatment Selection Treatment Adverse effects Cost Patient characteristics History of depression Weight gain concerns Breastfeeding Patient preference Precautions and contraindications Previous patient experience 22 Fiore et al. (2008). Treating Tobacco use and Dependence 24 6
Second Line Agents Pharmacotherapy Non FDA-approved Clonidine (Catapres, Catapres-TTS ) Nortriptyline (Pamelor ) 25 Fiore et al. (2008). Treating Tobacco use and Dependence 27 First Line Agents Nicotine Replacement Therapy (NRT) FDA-approved Nicotine Replacement Therapy (NRT) Nicotine Transdermal Patch (OTC) Nicotine Gum (OTC) Nicotine Lozenge (OTC) Nicotine Inhaler (Rx) Nicotine Nasal Spray (Rx) Buproprion SR (Zyban, Wellbutrin SR ) (Rx) Varenicline (Chantix ) (Rx) Fiore et al. (2008). Treating Tobacco use and Dependence 26 Fiore et al. (2008). Treating Tobacco use and Dependence Silagy, C., et al. (2004),. Cochrane Database Syst Rev CD000146 http://www.pharmahost.org/support/images/f/fd/nicotine_mechanism_of_action.gif 28 7
Nicotine Replacement Therapy (NRT) NRT Precautions Patch Options Gum, Inhaler, Lozenge Nasal Spray Recent MI (within 2 weeks) Serious underlying arrhythmias Serious or worsening angina pectoris Pregnancy category D Breastfeeding Adolescents (<18 years) Slow Absorption Intermediate Absorption Fast Absorption Fiore et al. (2008). Treating Tobacco use and Dependence Silagy, C., et al. (2004),. Cochrane Database Syst Rev CD000146 29 31 Nicotine Containing Products Plasma Concentrations Efficacy of NRT Rx for Change: Clinician-Assisted Tobacco Cessation. San Francisco, CA: The Regent of the University of California, University of Southern California, and Western University of Health Sciences.;1999-2008 30 All NRT forms increase quit rates at 6-12 months by 50-70% compared to placebo No significant difference between NRT forms 4mg gum is more effective in highly dependent smokers Higher dose patches do not show additional benefit The intensity of additional advice and support does not increase the effectiveness of NRT A combination of NRT products is more effective than one product alone Fiore et al. (2008). Treating Tobacco use and Dependence Silagy, C., et al. (2004),. Cochrane Database Syst Rev CD000146 Stead et al. (2008). Cochrane Database Syst Rev 2008(1) 32 8
Nicotine Transdermal Patch (NicoDerm CQ, etc.) Product NicoDerm CQ or generic 7mg, 14mg, 21mg (24-hour release) Adverse Effects Local skin reactions Headache Sleep disturbances Nicotine Transdermal Patch (NicoDerm CQ, etc.) Advantages Once daily dosing improves adherence Less visible Can be used in combination with other agents Delivers consistent nicotine levels over 24 hours Disadvantages Cannot be titrated to acutely manage withdrawal symptoms Not recommended for use in patients with dermatologic conditions (e.g., psoriasis, eczema, atopic dermatitis) Allergic reactions to adhesive 33 35 Nicotine Transdermal Patch (NicoDerm CQ, etc.) Dosing If >10 cigarettes/day: 21 mg/dayx 4-6 weeks 14 mg/dayx 2 weeks 7 mg/day x 2 weeks If <10 cigarettes/day: 14 mg/day x 6 weeks 7 mg/day x 2 weeks Counseling Points Worn for 24hr (16hrif having trouble sleeping) Apply upon awakeningon quit date Nicotine Gum (Nicorette, etc.) Product Nicorette or generic 2mg, 4mg Original, cinnamon, fruit, and mint flavors Adverse Effects Dyspepsia Sore mouth Hiccups Jaw ache Hypersalivation 4 weeks, then 2 weeks, then 2 weeks 34 36 9
Nicotine Gum (Nicorette, etc.) Nicotine Lozenge (Commit, Nicorette ) Dosing < 25 cigarettes/day: 2mg 25 cigarettes/day: 4mg 1 gum every 1-2 hours x 6 weeks 1 gum every 2-4 hours x 2 weeks 1 gum every 4-8 hours x 3 weeks Maximum 24 pieces/day Use up to 12 weeks Counseling Points Chew each piece slowly Park between cheek and gum when peppery or tingling sensation appears (~15-30 chews) Resume chewing when tingling fades Park in different areas of mouth Avoid acidic beverages15 minutes before and after chewing Product Commit or generic 2mg, 4mg Cherry or mint flavor Nausea Sore throat Hiccups Heartburn Headache Flatulence Insomnia Adverse Effects 37 39 Nicotine Gum (Nicorette, etc.) Nicotine Lozenge (Commit, Nicorette ) Advantages Oral substitute for tobacco Titrated to manage withdrawal symptoms Used in combination with other agents to manage craving Variations in flavors Disadvantages Frequent dosing can compromise adherence Proper chewing technique is necessary for effectiveness and to minimize adverse effects Dosing 1 st cigarette < 30 minutes after waking: 4mg 1 st cigarette > 30 minutes after waking: 2mg Weeks 1-6: 1 every 1-2 hours Weeks 7-9: 1 every 2-4 hours Weeks 10-12: 1 every 4-8 hours Maximum 20 lozenges/day Counseling Points Allow to dissolve slowly (20 30 minutes) Nicotine release may cause a warm, tingling sensation Do not chew or swallow Rotate to different areas of the mouth No food or beverages 15 minutes before or during use Used for at least 12 weeks 38 40 10
Nicotine Lozenge (Commit, Nicorette ) Nicotine Inhaler (Nicotrol Inhaler ) Advantages Can serve as an oral substitute for tobacco Can be titrated to manage withdrawal symptoms Can be used in combination with other agents to manage craving Disadvantages Frequent dosing can compromise adherence Gastrointestinal side effects Dosing 6 16 cartridges/day Individualize dosing Initially use 1 cartridge every 1 2 hours Use for up to 6 months Counseling Points Continuous puffing for 20 minutes Nicotine is depleted after 20 minutes of active puffing Inhale into back of throat or puff in short breaths Do NOT inhale into the lungs (like a cigarette) but puff as if using a pipe Open cartridge retains potency for up to 24 hours No food or beverages 15 minutes before or during use 41 43 Nicotine Inhaler (Nicotrol Inhaler ) Nicotine Inhaler (Nicotrol Inhaler ) Product Nicotrol Inhaler or generic 10 mg cartridge delivers 4mg inhaled nicotine vapor Adverse Effects Local irritation of mouth and throat Cough Headache Dyspepsia Rhinitis Advantages Can be titrated to manage withdrawal symptoms Mimics hand-to-mouth ritual of smoking Can be used in combination with other agents to manage cravings Disadvantages Frequent dosing can compromise adherence Cartridges might be less effective in cold environments Throat and mouth irritation Caution in patients with bronchospastic disease 42 44 11
Nicotine Nasal Spray (Nicotrol NS ) Nicotine Nasal Spray (Nicotrol NS ) Product Nicotrol NS or generic Metered spray 10mg/ml aqueous nicotine solution Adverse Effects Nasal irritation Nasal congestion Transient changes in taste and smell Headache Cough Sneezing Advantages Can be titrated to manage withdrawal symptoms Can be used in combination with other agents to manage situational urges Disadvantages Frequent dosing can compromise adherence Development of dependence Patients with chronic nasal disorders orreactive airway disease should not use spray Nose and throat irritation 45 47 Nicotine Nasal Spray (Nicotrol NS ) Bupropion SR (Zyban ) Dosing 1 2 doses/hour (8 40 doses/day) One dose = 2 sprays (one in each nostril); each spray delivers 0.5 mg of nicotine to the nasal mucosa Maximum: 5 doses/hour or 40 doses/day Use up to 3-6 months Counseling Points Prime prior to use Tilt head back slightly Do not sniff, swallow, or inhale through the nose as spray is being administered Wait 2 to 3 minutes before blowing nose Atypical antidepressant which inhibits dopamine and norepinephrine reuptake and possibly acts as a nicotinic antagonist Contraindications Seizure disorder Current or prior diagnosis of bulimia/anorexia Abrupt discontinuation of alcohol or sedatives/benzodiazepines MAO inhibitors in preceding 14 days 46 Hughes J et al (2004). Cochrane Database Syst Rev: CD000031 Zyban (Summary of Product Characteristics). 2009. GlaxoSmithKline 48 12
Bupropion SR (Zyban ) Bupropion SR (Zyban ) Precautions Hepatic impairment Concomitant therapy with medications/conditions known to lower the seizure threshold History of seizure Pregnancy category C BLACK-BOXED WARNING for neuropsychiatric symptoms Product Zyban or bupropion SR 150mg (sustained-release tablet) Adverse Effects Insomnia Dry mouth Nervousness/difficulty concentrating Nausea Dizziness Constipation 49 Hughes J et al (2004). Cochrane Database Syst Rev: CD000031 Zyban (Summary of Product Characteristics). 2009. GlaxoSmithKline 51 Efficacy of Bupropion SR (Zyban ) Bupropion SR (Zyban ) Combining bupropion SR with an NRT has been shown to increase short-term smoking abstinence rates Combination of bupropion SR and nicotine patch have shown no significant increase for long-term (>6months) abstinence rates compared to nicotine patch alone Dosing 150 mg every morning x 3 days, then 150 mg twice a day Do not exceed 300 mg/day Begin therapy 1 2 weeks prior to quit date Counseling Points Allow at least 8 hours between doses Avoid bedtime dosing to minimize insomnia Croghan IT et al. (2007) Randomized comparison of a nicotine inhaler and bupropion for smoking cessation and relapse prevention.. 2Piper ME et al (2009) Arch Gen Psych Ebbert et al. (2010). Drugs 2010; 70(6): 643-650 50 Hughes J et al (2004). Cochrane Database Syst Rev: CD000031 Zyban (Summary of Product Characteristics). 2009. GlaxoSmithKline 52 13
Bupropion SR (Zyban ) Varenicline (Chantix ) Advantages Twice daily oral dosing is associated with fewer adherence problems Might delay weight gain Beneficial in patients with depression Can be used in combination with NRT agents Disadvantages Increased seizure risk Several contraindications and precautions Patients should be monitored for potential neuropsychiatric symptoms Hughes J et al (2004). Cochrane Database Syst Rev: CD000031 Zyban (Summary of Product Characteristics). 2009. GlaxoSmithKline 53 http://www.euroclinix.co.uk/images/pages/how-varenicline-work.gif 55 Title Randomized trial of nicotine replacement therapy (NRT), bupropion and NRT plus bupropion for smoking cessation: effective in clinical practice Outcomes Self-reported cessation over 6 months with biochemical verification at 1 and 6 months Methods Open-label randomized controlled trial with 6 month follow up Participants: smokers (n=1071), NRT product of participant choice (n=418), bupropion (n=409), NRT plus bupropion (n=244) Results Abstinence rates for bupropion (27.9%) and NRT (24.2%) were not significantly different Abstinence rates for bupropion and NRT (24.2%) was similar to monotherapy Bupropion appears more beneficial than NRT in those with a history of depression (29.8 versus 18.5%) Conclusion Evidence has shown that bupropion is more beneficial than nicotine replacement therapy for smokers with a history of depression There is no difference in smoking cessation effectiveness among bupropion, nicotine replacement therapy, or their combination Stapleton J et al. Addict. 2013;108(12):2193-2201 54 Efficacy of Varenicline (Chantix ) Existing data indicates that varenicline is more effective than bupropion and some forms of NRT in achieving abstinence, and is recommended for use as a first line therapy Zwar N, et al (2007) Smoking cessation pharmacotherapy: An update for health professionals. 56 14
Varenicline (Chantix ) Varenicline (Chantix ) Precautions Use with caution and lower dosage in patients with CrCl<30 ml/min or those on dialysis Pregnancy category C Cardiovascular events BLACK BOX WARNING for neuropsychiatric symptoms Contraindications Hypersensitivity to varenicline Dosing Day 1-3: 0.5mg daily Day 4-7: 0.5mg twice daily Day 8-end of treatment: 1mg twice a day Counseling Points Take after eating with full glass of water to decrease nausea Take second pill at dinner rather than bedtime to reduce insomnia Cahill K et al (2007). Cochrane Database Syst Rev: CD006103 https://smokingcessationoption.com/images/img-recommended-dosing.gif 57 Varenicline (Chantix) Package insert. Accessed January 19, 2016 59 Varenicline (Chantix ) Varenicline (Chantix ) Product Adverse Effects Chantix 0.5mg and 1mg Nausea Sleep disturbance Vivid/strange dreams Headaches Constipation Vomiting Neuropsychiatric symptoms Advantages Twice daily oral dosing is associated with fewer adherence problems Different mechanism of action for patients who have failed other agents Disadvantages Should be taken with food or a full glass of water to reduce the incidence of nausea Requires monitoring for potential neuropsychiatric and cardiovascular symptoms Varenicline (Chantix) Package insert. Accessed January 19, 2016 58 Varenicline (Chantix) Package insert. Accessed January 19, 2016 60 15
Clonidine (Catapres, Catapres-TTS ) Title Efficacy of vareniclinecombined with nicotine replacement therapy vs. varenicline alone for smoking cessation Outcomes Primary outcome was the 4-week abstinence rates from smoking for weeks 9 through 12 of treatment Secondary outcome included point prevalence abstinence at 6 months, continuous abstinence rate from weeks 9 through 24, and adverse events Mechanism of Action Precautions Adverse Effects Stimulates alpha-2 adrenoreceptorsin the brainstem and reduces sympathetic outflow Rebound hypertension Pregnancy category C Dry mouth Drowsiness Dizziness Sedation Constipation Koefelenberg CFN et al. J Am Med. 2014. 312(2):155-161 61 63 Methods Randomized, blinded, placebo-controlled clinical trial with a 12-week treatment period and 12-week follow-up Four hundred forty-six generally healthy smokers were randomized (1:1); 435 were included in the efficacy and safety analyses Results Combination treatment was associated with a higher continuous abstinence rate at 12 weeks (55.4%vs 40.9%) and 24 weeks (49.0% vs32.6%) and point prevalence abstinence rate at 6 months (65.1%vs 46.7%) Clonidine (Catapres, Catapres-TTS ) Dosing Begin 3 days before quit date or on the quit date Tablet: 0.15-0.75 mg daily Patch: 0.1-0.2 mg per 24 hours (via appropriate strength patch applied once every 7 days) Counseling Points Applypatch to hairless location between the neck and waist Do not discontinue therapy abruptly Conclusion Vareniclinein combination with NRT was more effective than vareniclinealone at achieving tobacco abstinence at 12 weeks (end of treatment) and at 6 months Koefelenberg CFN et al. J Am Med. 2014. 312(2):155-161 62 64 16
Nortriptyline(Pamelor ) Efficacy of Nortriptyline (Pamelor ) Mechanism of Action Precautions Adverse Effects Blocks reuptake of norepinephrine and serotonin Risk of arrhythmias Use with caution in cardiovascular disease Avoid coadministration with MAOIs Pregnancy category D Sedation Dry mouth Blurred vision Urinary retention Lightheadedness Shaky hands Conflicting data exist regarding increased efficacy with combination therapy using nortriptyline and NRT compared to monotherapy 65 Ebbert et al. (2010). Drugs 2010; 70(6): 643-650 67 Nortriptyline (Pamelor ) Combination Therapy Dosing Begin 10-28 days before quit date Initially 25 mg daily, gradually increase to 75-100 mg daily Counseling Points Do not discontinue abruptly because of withdrawal effects Combination of NRT Long-acting formulation (patch) + short-acting formulation (gum, inhaler, nasal spray) Bupropion SR + nicotine patch Bupropion SR + varenicline Varenicline + NRT 66 68 17
Combination Therapy Increased abstinence rates Enhanced relief of withdrawal effects Considered in highest risk of relapse Previously failed monotherapy Smokers with high nicotine-dependence Heavy smokers (i.e. 20 cigarettes or more per day) Additional cost must be considered Ebbert JO, Hays JT, Hurt RD. Combination pharmacotherapy for stopping smoking: what advantage does it offer? Drugs 2010; 70(6): 643-650 69 Results At 12 weeks, 53% of the combination therapy group achieved prolonged and 56.2% achieved 7-day point-prevalence smoking abstinence, compared to 43.2% and 48.6% in varenicline monotherapy At 26 weeks, 36.6% of the combination therapy group achieved prolonged and 38.2% achieved 7-day point-prevalence smoking abstinence, compared to 27.6% and 31.9% in varenicline monotherapy At 52 weeks, 30.9% of the combination therapy group achieved prolonged and 36.6% achieved 7-day point-prevalence smoking abstinence, compared to 24.5% and 29.2% in varenicline monotherapy Participants receiving combination therapy reported more anxiety and depressive symptoms Conclusion Combined use of vareniclineand bupropion, compared with vareniclinealone, increased prolonged abstinence but not 7-day point prevalence at 12 and 26 weeks Neither outcome was significantly different at 52 weeks Ebbert JO et al. J Am Med. 2014.311(2):155-163 71 Title Combination Vareniclineand BuproprionSR for Tobacco Dependence Treatment in Cigarette Smokers: A Randomized Trial Outcomes Primary outcome was the prolonged (no smoking from 2 weeks after the target quit date) and 7-day point-prevalence (no smoking past 7 days), and abstinence rates at week 12 Secondary outcomes were prolonged and point-prevalence smoking abstinence rates at weeks 26 and 52 Methods Pharmacotherapy Use in Pregnancy Insufficient evidence for recommendations in pregnant smokers Category C: varenicline, bupropion SR Category D: nicotine replacement therapy Behavioral interventions are the preferred treatment Randomized, blinded, placebo-controlled multicenter clinical trial with a 12-week treatment period and 52-week follow-up Five hundred six cigarette smoking adults ( 18 years) were randomized and 315 (62%) completed the study Ebbert JO et al. J Am Med. 2014.311(2):155-163 70 72 18
Pharmacotherapy: Other Special Populations Role of the Pharmacist Pharmacotherapy is NOT recommended for: Assist in the selection of OTC products Smokeless tobacco users Smoking fewer than 10 cigarettes per day Adolescents OTC sales are restricted to adults 18 years or older Nicotine replacement therapy use in minors require a prescription Counsel on proper use of smoking cessation medications Assist physicians with evidence based recommendations Monitor drug interactions with smoking and smoking cessation therapy 73 Saba M et al. J Clin Pharm and Ther. 2014;39:240-247 75 Role of the Pharmacist Questions Ask about tobacco use Advise patient to quit Explain the risks and complications of tobacco use Promote and encourage smoking cessation Referral to a formal cessation program Encourage and provide support Saba M et al. J Clin Pharm and Ther. 2014;39:240-247 74 http://cdn.marksdailyapple.com/wordpress/wp-content/themes/marks-daily-apple-responsive/images/blog2/brainquestions.jpg 76 19
References : 2008 Update. Clinical Practice Guideline. Rockville, MD: USDHHS, PHS, May 2008. Stead LF et al. Nicotine replacement therapy for smoking cessation. Cochrane Review 2012, Issue 11 Ebbert JO, Hays JT, Hurt RD. Combination pharmacotherapy for stopping smoking: what advantage does it offer? Drugs 2010; 70(6): 643-650 Bullen C et al. Electronic cigarettes for smoking cessation: a randomised controlled trial. Lancet Sep 7 2013 Economic Facts About U.S Tobacco Production and Use. Centers for Disease Control and Prevention. [Accessed January 25, 2016]. Available at: http://www.cdc.gov/tobacco/data_statistics/fact_sheets/fast_facts National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health: The Health Consequences of Smoking. A Report of the Surgeon General.Atlanta, GA, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, May 27, 2004. Available at: http://www.cdc.gov/tobacco/data_statistics/sgr/2004/complete_report/index.htm.. Accessed January25, 2016. 77 References Silagy, C., et al., Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev, 2004(3): p. CD000146. Croghan IT et al. (2007) Randomized comparison of a nicotine inhaler and bupropion for smoking cessation and relapse prevention. Mayo Clin Proc. 82(2):186-95. Piper ME et al (2009) Arch Gen Psych 66(11):1253-1262. Baker TB, Breslau N, Covey L, Shiffman S: DSM criteria for tobacco use disorder and tobacco withdrawal: a critique and proposed revisions for DSM-5. Addiction 107(2):263 275, 2012 DiFranza, J.R.; Savageau, J.A.; Fletcher, K.; Ockene, J.K.; Rigotti, N.A.; McNeill, A.D.; Coleman, M.; Wood, C. (2002) Measuring the loss of autonomy over nicotine use in adolescents: Th e Development and Assessment of Nicotine Dependence in Youths (DANDY) Study. Archives of Pediatric Adolescent Medicine. 156:397-403. Heatherton, T.F.; Kozlowski, L.T.; Frecker, R.C.; Fagerström, K.O. (1991). Th e Fagerström Test for Nicotine Dependence: A Revision of the Fagerström Tolerance Questionnaire. British Journal of Addiction, 86 (9): 1119-27 Ebbert JO, Patten CA, Schroeder DR. Th e Fagerström Test for Nicotine Dependence- Smokeless Tobacco (FTND-ST). Addictive Behaviors 31(9), 2006, 1716-1721. Saba M, Diep j, Saini B et al. Meta-analysis of the effectiveness of smoking cessation interventions in community pharmacy. J Clin Pharm and Ther. 2014;39:240-247 78 20