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					    Pharmacological Treatments
      for Smoking Cessation
                        Allen Y. Masry, MD
            Assistant Professor –Addiction Psychiatrist
                     Department of Psychiatry
                 UMass Memorial Medical Center/
                      UMass Medical School




1
               Quick Facts
       Mental Illnesses & Tobacco
• 7.1% of the U.S. population has a psychiatric
   illness; however, this population consumes
      over 34.2% of all cigarettes. (Grant et al., 2004)
• In the U.S., persons with mental illnesses
   represent an estimated 44.3% of the tobacco
   market and are dependent at rates 2-3 x’s the
   general population. (Grant et al., 2004)
• Smoking quit rates for individuals with
   psychiatric illness are NOT significantly lower
      than the general population. (el-Guebaly et al., 2002)
 2
    Session goals:
       Some info on smoking and psychotropics
       Review of available medications for Smoking
        Cessation, both nicotine and non- nicotine.
       Role of medications in smoking cessation
        and maintenance of smoking.
       Review Smoking and SMI




3
4
     Ranking of nicotine in relation to
     other drugs in terms of addiction
Dependence             nicotine>heroin>cocaine>alcohol>caffeine
among users
Difficulty achieving   (alcohol=cocaine=heroin=nicotine)>caffeine
abstinence
Tolerance              (alcohol=heroin=nicotine)>cocaine>caffeine
Physical               alcohol>heroin>nicotine>cocaine>caffeine
withdrawal severity
Deaths                 nicotine>alcohol>(cocaine=heroin)>caffeine
Importance in          (alcohol=cocaine=heroin=nicotine)>caffeine
user's daily life
Prevalence             caffeine>nicotine>alcohol>(cocaine=heroin)

5
    Tobacco Effects on Psychiatric
    Medication Blood Levels
   Smoking induces the P450’s 1A2 isoenzyme
    secondary to the polynuclear aromatic hydrocarbons
   Smoking increases the metabolism of some
    medications
    –   Haldol, Prolixin, Olanzapine, Clozapine, Mellaril, Thorazine, etc
   Caffeine is metabolized through 1A2
   CHECK for medication SE or relapse to mental
    illness with changes in smoking status
   Nicotine does not change medication blood levels
    (2D6)
   NRT doesn’t affect medication blood levels
   Nicotine may modulate cognition, psychiatric
    symptoms, and medication side effects
6
    First-Line Medications
     Nicotine Replacement Therapy (NRT)
     -Patch (OTC)
     -Gum (OTC)
     -Lozenge (OTC)
     -Oral Inhaler (Rx)
     -Nasal Spray (Rx)
     Non-Nicotine Medications
     -Varenicline (Chantix, Rx)
     -Bupropion Hydrochloride (Rx)

7
8
    Reasons for Using NRT
     It works: roughly doubling success
      rates.
     It helps the person feel more
      comfortable (treats nicotine
      withdrawal syndrome).
     It is very safe: the person is getting
      “clean” nicotine instead of “dirty”
      nicotine with 4000 plus chemicals.
9
     Nicotine withdrawal
                     Withdrawal syndrome
                      is a collection of signs
                      and symptoms
                      caused by abstinence

                     Nicotine or cigarette
                      withdrawal?

                     Nicotine replacement
                      reduces severity of
10                    withdrawal symptoms
     Sign of Nicotine Toxicity
 • Extremely RARE IN SMOKERS & thus
   even more rare in NRT use.
 • Nausea and/or vomiting
 • Sweating
 • Vertigo and/or Light-headedness
 • Tremors
 • Confusion
 • Weakness
 • Racing heart
11
 Nicotine Patch
          Dosing:                    Pros:
                                      -Easy, good
          < 10 cigs/day: 14 mg        compliance
           patch                      -Continuous
                                      nicotine
          ≥ 10 cigs/day: 21 mg        delivery
           patch                      -OTC
        Length of Treatment:          Cons:
                                      -Slow onset
        Up to 12 weeks (PDR)          of action
        Use:                          -Skin
        Apply to clean skin area      reaction,
                                      Insomnia
        (upper trunk/ arms)
        24 or 16 hour dosing, try
        24 to dec. morning craving
        Watch for nightmares
        Given with or without taper
12
  Nicotine Gum
                          Dosing:
                           2mg < 25 cigarettes/day
                           4mg > 25 cigarettes/day
                         Length of Treatment:
                          8-10 weeks (PDR)
Use: Chew and park (oral absorption)
        Slow, buccal absorption
        Acidic foods ↓ absorption
Pros: Flexible dosing (every 1-2 hours, up to 24
        pieces/day)
        Keeps mouth busy
        OTC
Cons: Need to use correctly (chew and park)
         Nausea, Heartburn
13       Mouth and throat burning
14
 Nicotine Lozenge
                         Dosing:                       Length of
                         Based on Time To First         Treatment:
                         Cigarette (TTFC)                 12 weeks
                         4 mg ≤ if 30 mins TTFC         (PDR)
                         2mg > if 30 mins TTFC

    Use: Allow to dissolve (Don’t Chew but Suck like a hard candy.)

    Pros: Flexible dosing (Up to 20 lozenges/ day)
           More discreet than gum; Keep mouth busy; OTC;

    Cons: Need to use correctly (don’t chew, suck)
           May cause insomnia, some nausea,
15         hiccups, heartburn, coughing
     Nicotine Nasal Spray
                Dosing:
                 1-2 doses per hour
                 1 does = 2 spays (1 spray/nostril)
                 Use enough to control withdrawal
                 symptoms


                Length of Treatment:
                 3-6 months weeks (PDR)


16
     Nicotine Nasal Spray
    Use: Spray (don’t sniff, swallow, or inhale)
           PRN or fixed-schedule (1-2 doses/hour)
    Pros: Rapid delivery though nasal mucosa
           Flexible dosing (up to 40 doses)
    Cons: Nasal irritation, rhinitis, coughing, &
           watering eyes.
           Some dependence liability
           Rx needed

17
     Nicotine Medications
      Use high enough dose
      Scheduled better than PRN
      Use long enough time period
      Can be combined with Bupropion
      Don’t combine with Varenicline
      Can be combined with eachother
      Have very few contraindications
      Have no drug-drug interactions
18
     Efficacy of NRT medications

     2.5                                         2.27
               1.73    1.66    1.76      2.08
      2

     1.5

      1

     0.5

      0
                Odds Ratio of 6 month abstinence

           Overall    Gum   Patch     Inhaler   Nasal spray

19
     Withdrawal Symptoms and NRT

                               ***           ***   ***         ***
                         200
                               *             ***    N.S.


                         150   N.S.          **
      Total Withdrawal




                                      N.S.
                                                                                        *    P < 0.05
                                                                                        ** P < 0.01
                         100
                                                                                        *** P < 0.001




                                                                       Placebo
                          50


                           0
      Total withdrawal in mm (calculated by averaging each symptom over the 11 ratings and adding the 9
      symptoms) for the 4 treatments and baseline smoking with P-values adjusted for multiple testing
      (Bonferoni correction).
20                                                   Adapted from: Fagerström et. al. Psychopharmacology, 1993,
                                                     111:3, 271-7
     Some strategies
   Recommended doses of nicotine replacement
    therapy are inadequate for many smokers
   In heavy smokers, under dosing may limit the
    effectiveness of patch
   Patch plus Gum
     – Improves abstinence rates (Kornitzer 1995,
       Puska 1995)
     – Decreased withdrawal (Fagerstrom 1993)
     – Well tolerated
   UMass uses up to 42mg patch or patch plus

21 GUM
     Odds Ratios for the Efficacy of
        Higher Doses and NRT
            Combinations

 Gum (4mg vs 2 mg)     1.98 (1.30-3.00)
 Patch (21mg vs 14)    1.27 (1.03-1.57)
 Comb vs single ttt    1.64 (1.22-2.21)
 Comb vs patch only    1.87 (1.17-2.99)

22
     Smoking with NRT
      Relatively safe
      Harm Reduction
      Less reinforcing effects
      Not a distraction from quit
       attempts
      (Benowitz 1997, Hartman 1991, Slade 1995)


23
     Smoking and NRT: IS THAT SAFE?
         Concern about this is not supported by data.
         Joseph took a high risk cardiac group and put them
          on patch or placebo.
           –   49% with active angina
           –   40% with history of heart attack
           –   35% with history of cardiac bypass
           –   No increase in cardiac events for the patient group
           –   21% of the patients were not smoking at the end vs 9% of the
               placebo group.
           –   Jiminez-Ruiz put severe COPD patients on nicotine gum
           –   Most patients continued to smoke, though less.
           –   No adverse events attributed to nicotine.
           –   COPD (chronic obstructive pulmonary disease) got better

          (Joseph AM. NEJM 335:1792-8, 1996 & Jiminez-Ruiz.   Respiration 69:452-6, 2002)
      Slide copied from OASAS.

24
     Conclusions
     Nicotine Replacement Therapy is being
      provided to assist tobacco users to
      become tobacco free.
     NRT is not a treatment in itself, but is
      intended to complement the other
      assessments and treatments provided.
     NRT works by reducing craving and
      withdrawal severity, enabling the
      patient to feel comfortable and able to
      concentrate on other psychosocial
      treatments.
25
     Non-Nicotine Pharmacotherapy

      First-line non-nicotine medications
        -Bupropion (Zyban/Wellbutrin)**
        -Varenicline (Chantix)**
      Others (nortriptyline, clonidine)



                          **FDA Approved for smoking cessation



26
     Bupropion Hydrochloride
        Dopamine and norepinephrine (noradrenaline)
         effects
        Reduces cravings, withdrawal
        Improved abstinence rates in trials
        Less weight gain while using (Need to gain
         100 pounds to diminish health benefit)
        Start 7-10 days prior to quit date
        Continue 7-12 weeks or longer
         ( > 6 months)
27
     Bupropion Precautions
        Contraindicated: seizure disorder, eating
         disorders, electrolyte abnormalities, MAO
         use
         –   OK with SSRIs
        NOT dangerous to smoke while taking
        Monitor blood pressure
        Side effects:
         –   Insomnia (40%)
                 2nd dose early evening helps
         –   Dry mouth
         –   Headaches
         –   Rash
28
          Bupropion Efficacy
     50
                        *
                    *
     40
                                                   Placebo
     30                                            100 mg
                                         *   *
     20                                            150 mg
                                                   300 mg
     10

      0
           7 week abstinence   1 year abstinence


29                                                 Hurt, 1997
Varenicline (Chantix)

 Action at 42 nicotine receptor
 Partial agonist/antagonist
 Releases lower amounts of dopamine
  into brain than smoke
    –   Reduces withdrawal
    –   Not as addictive as smoke
   Blocks nicotine from binding to receptor
    –   Prevents reward of smoking
     Varenicline (Chantix)

      Action at 42 nicotine receptor
      Partial agonist/antagonist
      Releases lower amounts of dopamine
       into brain than smoke
         –   Reduces withdrawal
         –   Not as addictive as smoke
        Blocks nicotine from binding to receptor
         –   Prevents reward of smoking
31
     Dosing
                     Titrate dose from 0.5
                      mg daily to twice daily
                      to 1 mg twice daily over
                      1 week
                     Abstinence rates better
                      vs. placebo and
                      Bupropion at 1 year
                     Optimal duration 12-24
                      weeks
        CHX 0.5      Most common side
        Pfizer
                      effect is nausea
32
     Abstinence by medication use
     100%
                                                             82%
     80%                                         74%
                                     64%
     60%                 52%
                                                       42%         42%
                               37%         37%
     40%    31%
                  20%
     20%

      0%
            No meds       1 med      2 meds      3 meds      4+ meds

                      4-week abstinence    6-month abstinence
33
     Serious Mental Illness

        Reduced Cessation
         -Schizophrenia/Schizoaffective disorder
         -Bipolar disorder
         -PTSD
         -Alcohol use disorder


34
     Smoking and
     Schizophrenia
      High prevalence of smoking (about
       90%, OR = 5.9)
      Highly nicotine dependent (FTND = 7
       or higher)
      Nicotine produces cognitive or other
       benefit
      Smoking ameliorates medication side
       effects (e.g., lower rates of
       neuroleptic-induced Parkinsonism)
35
     Smoking and Schizophrenia
     (Continued)
         Smokers with schizophrenia take in
          more nicotine per cigarette than
          smokers without this disorder
         Higher levels of positive symptoms
          and decreased negative symptoms
         Ad libitum smoking increases after
          initiation of haloperidol
         SCZ tend to smoke less on clozapine

36
     Neurobiology of Smoking
     and Schizophrenia
      Decreased low affinity and high affinity
       nAChRs
      Abnormal P50 responses are
       normalized
      Improved Spontaneous Pursuit Eye
       Movement and decreased Saccades
       with nicotine
      Improved cognition and attention

37
 Smoking & Bipolar Disorder
  High prevalence of smoking: 61-80%
  Findings are inconsistent regarding
   the prevalence of smoking between
   bipolar disorder with and without
   psychotic features
  Bupropion is contraindicated
  Quit rates are comparable to general
   population and durable
  Quit rates enhanced with CBT


38
         Smoking and Depression
        The prevalence of smoking: 37-60%
        Leads to more severe nicotine withdrawal
         symptoms
           - High risk for relapse in first week
           - Female > Male
        30% risk of relapse to MDE after quitting if
         past history present
         Depressed smokers have higher suicide
         rates than depressed nonsmokers
            (Bruce, 1994; Lohr, 1992; Yassa, 1987)




39
         Link Between MDD and
         Smoking

                      60

                      50

         Lifetime     40
      Prevalence of
          Major       30
     Depression (%)
                      20

                      10

                      0
                           None     1 to 5     6 to 10    11 to 20      >21
                                  Average Daily Cigarette Consumption


                                                  Adapted from Kendler KS, 1993
40
   Smoking and Depression (Continued)

    NRT alone insufficient treatment for
     smokers with current and/or past MDD
    Combining NRT with non-NRT
     pharmacotherapy appear to be
     promising for smokers with depression
     (Ait-Daoud et al., 2006)
    CBT that emphasizes group cohesion
     and social support appears to be
     particularly effective for depressed
     smokers with or without alcohol
41
     dependence
      Smoking and Anxiety D/O
    The prevalence of smoking: About 35-50%
    Smokers have greater anxiety and panic symptoms
     than non-smokers
    Heavy smoking in adolescent is associated with
     higher risk of developing Agoraphobia, GAD, and
     Panic Disorder
    PTSD:
     –   Increased risk for relapse in first two weeks of quit attempt
     –   Increased the risk of smoking and nicotine dependence
     –   lower rates for quitting smoking & remission from nicotine
         dependence
     –   Stopping smoking not associated with worsening of PTSD
     –   Bupropion tolerated and effective treatment
42
     SSRIs and Smokers with
     Anxiety Disorder
      No benefit for smoking cessation
      Can reduce likelihood of emergent
       anxiety and panic during quit attempt
      Bupropion is not appropriate as only
       medication
      Can be combined with NRT/Bupuropion
      Can be combined with varnicline


43
    Smoking and Alcohol
    Dependence
    High prevalence of smoking: 80-95%
    Two studies reporting similar outcomes
     of NRT in alcoholics compared with non-
     alcoholics (e.g., Grant et al., Alcohol,
     2007)
    Tobacco dependence treatment does
     not cause abstinent alcoholics to relapse
     (Hughes & Callas, 2003)
    Smoking cessation reduces the risk of

44
     alcohol relapse (Sobell et al., 1995)
         Smoking and Alcohol Dependence
         (Continued)

      Bupropion added to nicotine patch did
       not improve smoking outcomes
      Topiramate group was significantly
       more likely to become abstinent (OR =
       4.46) compared with placebo group
       (Johnson et al., 2003)
      Topiramate group reported more weight
       loss compared with placebo group
       (44% vs. 18%)

45
                                     Percentage of Patinets With or Without Specific Metal Illness
                                      Who Had Quit Smoking at the end of Tobacco Dependence
                                                             Treatment

                                45
                                             39.6    39.3
                                40                                         37               37
     Percent Who Quit Smoking




                                                            36      35.9
                                                                                      34
                                35
                                30
                                25                                                                     With Diagnosis
                                      20.5
                                20                                                                     Without Diagnosis
                                15
                                10
                                 5
                                 0
                                     Schizophrenia   Bipoloar          MDD             PTSD
                                                     Disorder
                                                       Psychiatric Disorders




46                                                                      Adapted from Grand et al., J Clin Psychiatry, 2007
     Benefits of Treating Tobacco
     Dependence in Mental Healthcare
     Settings
      Emerging evidence shows that
       morbidity is reduced
      May enhance abstinence from other
       substances
      Reduced financial burden
      Increased self-confidence




47
     Conclusions

      Pharmacotherapy   works and is
       relatively safe
      Many options now available
      Patients should be given accurate
       expectations (no magic bullet)



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