Pharmacologic Therapy for Tobacco Use & Dependence · ©2011 MFMER | slide-1 Pharmacologic Therapy...

©2011 MFMER | slide-1

Pharmacologic Therapy for Tobacco Use & Dependence

Jon O. Ebbert, MDMayo ClinicNicotine Dependence CenterRochester, MN


Learning Objectives• Identify medication options for the treatment

of tobacco dependence

• Identify dosing, contraindications, and adverse events associated with pharmacotherapies for the treatment of tobacco dependence

DisclosuresRelevant Financial Relationship(s)Name Nature of Relationship Company NameJon Ebbert, M.D. Consultant Nesmah

Stock Shareholder (self-managed) Al Kaif

Off Label/Investigational UsageNone

Rationale for Pharmacological Therapy• Attenuate reinforcing effects

• Positive reinforcement• Negative reinforcement

• Reduce urges to smoke• Break the link between nicotine effects and

environmental triggers• Engage strategies to change smoking

behavior

Combined Behavioral & Pharmacotherapy

• Odds of successful abstinence at 6 months or longer with combined therapy compared with behavioral or pharmacotherapy alone

• Overall 1.82 (1.66, 2.00)• Health care setting 2.06 (1.81, 2.34)• Community setting 1.53 (1.33, 1.76

Stead, LF and Lancaster, T. Combined pharmacotherapy and behavioral interventions for smoking cessation. 2012 Cochrane Review


© 2004 MAYO CLINIC COLLEGE OF MEDICINE ALL RIGHTS RESERVED

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USPHS Guideline Recommendations• First-Line

• Nicotine Replacement Therapy• Gum• Patch• Inhaler• Nasal Spray• Lozenge

• Non-NRT• Bupropion SR• Varenicline


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Nicotine Gum

• Useful adjunct with intervention• Most effective with counseling• 2 mg and 4 mg• “Chew and Park”• Frequent use initially (10-15/day)• Frequently used in combination with other

NRT


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Nicotine Patch• Standard: 21 mg for 6 weeks, 14 mg for 4

weeks, 7 mg for 2 weeks• Start on target quitting date• Evidence of need for tapering at end of

treatment is minimal• Treatment for minimum of 8 to 12 weeks


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Nicotine Patch Therapy: Dosing Guidelines

Based on Baseline Cigarettes/Day1 mg per 1 cigarette/day

<10 CPD 7-14 mg/d10-20 CPD 14-21 mg/d21-40 CPD 22-42 mg/d>40 CPD 42+ mg/d


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Nicotine Nasal SprayClinical Use

• More rapid delivery & more rapid treatment of withdrawal than other nicotine preparations

• 1 spray = 0.5 mg nicotine• 1 dose = 1 spray in each nostril (Total = 1 mg)• Instruction is important

• Spray against lower nasal mucosa - don’t sniff

• Recommend:• 1-2 dose/h• NTE 5 doses/h or 40 doses/d


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Nicotine Lozenge• Nicotine Lozenge

•2 mg•4 mg

• Dissolves in mouth over 20-30 minutes

• Delivers 25% more nicotine than the gum


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Adverse events related to nicotine replacement therapyMills EJ, Wu P, Lockhart I, et al. Tobacco Induced Diseases 2010;8(8):1-57

Adverse event Prevalence in observational studies (%)Skin irritation 19.5 PATCHInsomnia 11.4Headache* 9.7Nausea or vomiting 8.5Cough 8.1 NASAL SPRAYDizziness* 7.3Mouth/throat irritation 5.4 GUM/LOZ/INHALERGI complaints 3.9Heart palpitations 3.6Anxiety* 2.9Depression* 2.6Hiccoughs 2.5

*In RCT’s no difference in AE rate in active compared with placebo treatment

NRT Contraindications• Virtually none• Serious allergic reaction (rare)• Blistering patch site reactions


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USPHS Guideline Recommendations

• First-Line• Nicotine Replacement Therapy

• Gum• Patch• Inhaler• Nasal Spray• Lozenge



Mechanism of Action• Atypical antidepressant• Blocks reuptake of NE and DA• Increased DA in the mesolimbic “reward center”

mimics nicotine• Uncertain of NE role in smoking cessation• May act as a nicotinic receptor blocker


Bupropion Efficacy Across Populations• Psychiatric comorbidity (PTSD, schizophrenia,

on SSRI for MDD)• Medical comorbidity (COPD, CHD)• Urban African-Americans• Bupropion significantly increases long-

term cessation• 44 trials, N = 13,728, risk ratio • RR 1.62 (95% CI: 1.49 -1.76)

Hughes JR, et al. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2014 Jan 8;(1):CD000031.


Bupropion SR prescribing• Set target quit date 1 week from start

of medication• Begin with 150 mg daily for 3 days• Increase to 150 mg twice daily at least

8 hrs apart• Evening dose before 6PM• Treat for 8-52 weeks


AE Mean % Range StudiesInsomnia 32.3 10 to 53 25Dry mouth 23.9 6 to62 17Headache 21.5 6 to 56 9Diarrhea 17.5 6 to 50 5Anxiety 20.3 10 to 31 4Nausea 19.8 10 to 44 5

Common adverse events reported in 40 controlled clinical trials of bupropion SR


Serious adverse effects with bupropion SR• Seizure rate about 1/1000 treated

• 7/6409 subjects on active therapy in RCT’s• Post marketing studies show seizures in people

with known predisposition• Contraindications: known seizure (ever); structural

brain abnormality; serious closed head injury• Hypersensitivity (about 1%)

• Hives, urticaria, angioedema• Serum sickness-like

• Neuropsychiatric symptoms (“Boxed Warning”)

Bupropion contraindications• Allergic reaction (occurs in about 1%)• Anorexia/bulimia• Seizure history or seizure risk

• Withdrawal seizures• Febrile seizures• Serious closed head injury (LOC within 5

years or evidence of intracranial injury)• MAO inhibitors• Liver failure



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USPHS Guideline Recommendations

• First-Line• Nicotine Replacement Therapy

• Gum• Patch• Inhaler• Nasal Spray• Lozenge



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Varenicline Mechanism of Action

• Varenicline targets the nicotinic acetylcholine receptor

• Not nicotine nor an antidepressant• Partial agonist with specificity for the α4β2

acetylcholine receptor• Agonist - stimulates the receptor to

decrease craving and withdrawal• Antagonist - blocks the receptor to

decrease the reinforcement associated with smoking

• No clinically relevant drug-drug interactions

NH

NN

Varenicline

Acetylcholine receptor

http://www.cnsforum.com/content/pictures/imagebank/hirespng/hrl_rcpt_sys_nic_ACH.png


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©2011 MFMER | 3136593-34

Varenicline Prescribing• Use in combination with behavioral treatment• Start medication 1 week prior to target quit date

• Days 1-3, Varenicline 0.5mg daily • Days 4-7, Varenicline 0.5mg twice daily• Day 8 to end of treatment 1.0mg twice daily• TQD on day 8

• Take with food and 8-12 ounces of water • Dose reduction with severe renal impairment (GFR<30) • Supplied as starter card (11X0.5mg tabs) and 4-week

packs of 1 mg BID or bottles of 56• Treat for 3 to 6 months

©2011 MFMER | 3136593-35

Additional Prescribing Information• No dose reduction needed in…

• Geriatric population• Patients with liver disease

• No important drug-drug interactions• Reduce dose in renal impairment

• Estimated creatinine clearance <30 ml/min reduce dose to 0.5 mg daily and titrate to0.5 mg BID as tolerated

©2011 MFMER | 3136593-36

Common Adverse Events in Clinical Trials (%)

Varenicline Placebo

Nausea 35.8 11.2

Insomnia 22 12.7

Abnl dreams 14.4 5

Headache 16.8 14.3

Other GI 22.5 11.8

Discontinued 12 8.1


Anthenelli RM, et al. . Lancet. 2016 Jun 18;387(10037):2507-20. PubMed PMID: 27116918.







©2011 MFMER | 3136593-41

Varenicline and Neuropsychiatric Symptoms• Advise patients and family members that this

has been observed

• Ask patients and/or family to report any symptoms like this to you

• Patients with serious psychiatric comorbidity were not included in clinical trials

• No cause and effect relationship has been established

Cochrane Review of NRT

RandomizationSmokers

Varenicline + Bupropion SR

Varenicline + Placebo

Medication: 12 weeks total with standard “ramp up”

Study Design

Conclusions• For lighter and less dependent smokers,

varenicline+bupropion SR does not increase smoking abstinence rates compared to varenicline alone.

• For heavier and more dependent smokers, varenicline+bupropion SR significantly increases smoking abstinence rates compared to varenicline alone.


Pharmacotherapy for Tobacco Dependence: General Approach

Non-NRT

Bupropion SR

or

Varenicline

NRTContinuous dosing

Patches @ 1 mg patch per 1 cigarette per day

Ad lib dosing

Gum

Inhaler

Nasal spray

Lozenge



“Reduce-to-Quit”• Viable option for smokers unwilling to set a

target quit date right away• Use pharmacologic support during reduction• Advise a specific reduction schedule/target• Continue treatment even for those who miss the

target quit date if motivated to quit


Learning Objectives• Identify medication options for the treatment

of tobacco dependence

• Identify dosing, contraindications, and adverse events associated with pharmacotherapies for the treatment of tobacco dependence

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