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Nicotine Addiction In the Psychiatrically Ill

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Title: Nicotine Addiction In the Psychiatrically Ill


1
Nicotine Addiction In the Psychiatrically Ill
  • Kumar Maharaj, R.Ph, BCPP

2
Epidemiology
  • Schizophrenia 58-92
  • Major Depression 31-61
  • Smokers with psychiatric disorders consume nearly
    40-50 of all cigarettes consumed in the United
    States.1-5
  • Shared underlying neurobiology?

1) Poirier MF, Canceil O, Bayle F, et al. Prog
Neuropsychopharmacol Biol Psychiatry 2002
26529-537. 2) Breslau N, Johnson EO, Hiripi E,
Kessler R. Arch Gen Psychiatry 2001
58810-816.3) Haustein KO, Haffner S, Woodcock
BG. Int J Clin Pharmacol Ther 2002 40404-418.
4) de Leon J, Tracy J, McCann E, et al.
Schizophr Res 2002 5655-65. 5) Lasser K,
Wesley BJ, Woolhandler S, et al. JAMA 2000
2842606-2610.
3
Outpatient EpidemiologyHughes JR. Am J
Psychiatry 143993-7, 1990.
  • Looked at 277 outpatients
  • 88 of schizophrenics smoked.
  • 70 of patients with mania
  • 49 of major depressives
  • Anxiety and personality disorders 45-7
  • Controls 30
  • This was 20 years ago. More recent figures put
    the US general population at 23.

4
Smoking Patterns
  • Smokers with a SMI tend to
  • Smoke heavily (gt25 cigs/day).
  • Smoke efficiently (achieve higher cotinine).
  • Experience increased symptoms
  • Experience increased hospitalizations
  • Ziedonis D, Williams JM, Smelson D Am J Med Sci
    2003326(4)223-230

5
Overall MortalityHannerz. Pub Health
115328-37, 2001
  • The life expectancy of patients with
    schizophrenia is 10 years less than the general
    population.
  • Age adjusted death due to pulmonary disease is
    significantly elevated for schizophrenics.

6
Nicotine and Neuropharmacology
  • Given the widespread effects of tobacco and its
    withdrawal on human brain and neurotransmitter
    activity, it is perhaps not surprising that
    tobacco is associated in various ways with a
    number of mental disorders. What is perhaps more
    surprising is how often these effects continue to
    be ignored in both the clinical management and
    research into these disorders. Foulks J. The
    relationship between tobacco use and its mental
    disorders. Curr Opin Psychiatry 12303-6, 1999.

7
What Does Nicotine Do? I
  • Nicotine is structurally similar to
    acetylcholine.
  • Nicotinic acetylcholine receptors are widely
    distributed.
  • Nicotine leads to
  • Increased firing of DA neurons in
    mesocorticolimbic pathways.
  • This leads to increased release of DA in the
    nucleus accumbens (negative symptoms) and
    prefrontal cortex (sensory gating).

8
What Does Nicotine Do? II
  • Release of DA in the nucleus accumbens has been
    associated with reward.
  • DA is released in this area during the
    anticipatory part of eating and sexual behaviors.
  • This burst firing is normally under the control
    of excitatory cells from the prefrontal cortex.
  • There is evidence of hypofrontality (anhedonics)
    with schizophrenia.
  • Human smokers have a 40 ? in MAO B activity.
  • Thus, we have ? DA release and ? DA metabolism.

9
What Does Nicotine Do? II
  • Actions similar but more limited than cocaine.
  • Cocaine blocks the dopamine transporter.
  • Nicotine may shut down the nicotine
    receptor-effect is limited to short bursts.
  • May lead to up-regulation over time.

10
Dopamine Hypothesis of Schizophrenia
Hypoactivitynegativesymptoms
Hyperactivitypositivesymptoms
Adapted from Inoue and Nakata. Jpn J Pharmacol.
200186376.
11
Psychopathology Smoking Goff Am J Psychiatry
1491189-94, 1992.
  • 78 OPs w/ schizophrenia. 74 were smokers.
  • Smokers had
  • higher BPRS scores (for both positive negative
    sx)
  • earlier onset
  • more hospitalizations
  • drank more caffeine
  • more likely to be men.
  • Smokers had less EPS even on twice the dose.

12
Barriers to Quitting Smoking for Pts w
Schizophrenia
  • Severe nicotine withdrawal-overlap with core
    symptoms
  • Potential increase in negative symptoms.
  • Attention concentration e.g. sensory auditory
    gating.
  • Lack of alternative reinforcers for abstinence.
  • Cognitive limitations in learning self-management
    skills.

13
Barriers to Quitting Smoking for Pts w
Schizophrenia
  • Clinician inattention
  • Difficulty in accessing smoking cessation
    programs.
  • Low motivation to quit (precontemplation?)
  • Enabling treatment systems and providers
  • Poor social skills
  • Difficulty forming social alliances

14
Hypotheses--Social
  • Smoking becomes a major part of daily routine and
    affords structure.
  • Cigarettes historically used as a reward in
    treatment centers.
  • SPMI patients have been removed from larger
    societal efforts to curb smoking-remember they
    buy the majority of cigarettes.

15
HypothesesSelf-Medication
  • Particularly for negative symptoms (affective
    flattening, alogia, avolition).
  • Increased DA activity in frontal lobes.
  • 77 of pts smoke before first treatment.
  • Depressed pts have many of the same negative sx,
    but smoke far less than pts with schizophrenia.

16
HypothesesReduction of Med Toxicity
  • Tobacco is a potent inducer of 1A2 and 2E1 P450
    isozymes.
  • Prodopaminergic function could reverse DA
    blockade.
  • The fact that first break smokers smoked the same
    as neuroleptic veterans argues against this.

17
Typicals, Atypicals, Smoking--InterpretationMcE
voy JP. Biol Psychiatry 46125-9, 1999
  • The fact that neuroleptic naïve patients smoke at
    the same rate as neuroleptic veterans argues
    against smoking to reverse DA blockade.
  • It does support a substitution hypothesis.
  • Nicotine was helping with signs and symptoms of
    schizophrenia.
  • When CLO helped, there was less need for nicotine.

18
Nicotine, Sensory Gating, and Atypicals
  • Nicotine normalizes a deficit in auditory sensory
    gating.
  • This deficit, associated with difficulty in
    censoring out extraneous information is not
    corrected by typical antipsychotics.
  • It is corrected in atypical responders.

19
NonDA Effects of Nicotine
  • Acute administration of nicotine increases 5-HT
    release.
  • Chronic administration leads to a decrease in
    5-HT synthesis.
  • Post-mortems with human smokers shows a decreased
    concentration of 5-HT and 5-HIAA.

20
Special Challenges
  • Assessment
  • Engagement into treatment
  • Medication treatments
  • Psychosocial treatments
  • Program level interventions

21
Special Challenges
  • Assessment
  • All clients must be screened at all levels of
    care
  • The 5 As
  • Ask
  • Advise
  • Assess
  • Assist
  • Arrange

22
Special Challenges
  • Engagement into treatment
  • Physician advice
  • Stages of change
  • Precontenplation 50-60
  • Reluctant precontemplators-resists change out of
    fear
  • Rebellious precontemplators-opposed-its my right
  • Resigned precontemplators-failed in prior
    attempts
  • Rationalizing precontemplators-my _ smoked 3 pks
    lived
  • Contemplation 30-40
  • Preparation
  • Action 10-15
  • Maintenance

23
Special Challenges
  • Engagement into treatment
  • Motivational Interviewing The approach is client
    centered respectful, compassionate with a
    mixture of open-ended questioning and empathic
    listening.
  • Roll with resistance like judo
  • Express empathy empathy conveys understanding
  • Develop discrepancy current versus ideal
    behavior
  • Support self-efficacy support autonomy

24
Special Challenges
  • Medication treatments
  • Underutilized
  • Under dosed

25
Special Challenges
  • Psychosocial treatments
  • The patient should know what to expect
    withdrawal, weight gain, medication changes,
    money saved, better health.
  • Problem solving
  • Groups-what type, how long?
  • Motivational enhancement
  • Where???

26
Special Challenges
  • Program level interventions
  • RFA

27
Somatic Treatments
  • Pharmacotherapies can be divided into
  • Replacement therapy.
  • Antagonist therapy.
  • Aversion therapy.
  • Non-nicotine medications that mimic nicotine
    effects.
  • Non-medication somatic therapies include
    acupuncture and devices.

28
Cochrane Reviews
  • Objectives To determine the effectiveness of
    different strategies.
  • Outcome Measures Abstinence from smoking after
    gt 6 months.

29
Aversive Therapy
  • Pairs a pleasant stimulus with an unpleasant
    stimulus.
  • InclusionRandomized trials which compared
    aversion txments with inactive procedures.
  • Or
  • Aversion txments of different intensity.

30
Aversive Smoking
  • Results
  • 25 trials met inclusion criteria.
  • Existing studies provide insufficient evidence to
    determine efficacy
  • Odds Ratio for abstinence
  • 1.98 Active
  • 1.36 Controls

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Hypnotherapy
  • Randomized trials with 6 month data.
  • 9 studies.
  • Hypnotherapy does not have a greater effect on 6
    month quit rates than no treatment.

58
Acupuncture
  • 22 Studies.
  • Odds ratio vs sham treatments.
  • 1.5 after 6 months.
  • 1.09 after 12 months.

59
Silver Acetate
  • 2 studies-silver acetate vs placebo.
  • Odds ratio 1.05.

60
Mecamylamine
  • 2 small studies
  • Nicotine plus mecamylamine 40
  • Nicotine 20
  • Mecamylamine 15
  • No active drug 15

61
Opioid Antagonists
  • Naloxone and naltrexone.
  • 2 trials-more since.
  • No difference vs placebo.

62
Anxiolytics
  • Agents studied
  • Diazepam
  • Meprobamate
  • Metoprolol
  • Oxprenol
  • Buspirone
  • No evidence of efficacy

63
Clonidine
  • 6 trials 3 oral, 3 transdermal
  • All participants received counseling
  • Pooled odds ratio 1.89 vs placebo
  • Prominent side effects
  • Dry mouth
  • Sedation

64
Antidepressants
  • Bupropion (5)
  • Doxepin (1)
  • Fluoxetine (2)
  • Imipramine (1)
  • Moclobemide (1)
  • Nortriptyline (2)
  • Selegiline (1)
  • Sertraline (1)
  • Tryptophan (1)
  • Venlafaxine (1)

65
Results
  • Nortriptyline and Bupropion aid smoking cessation
  • Other agents role?

66
NRT
  • Aim To assess the effectiveness of
  • Nicotine Gum
  • Transdermal patches
  • Nasal Spray
  • Inhalers

67
NRT
  • Aim To determine if NRTs efficacy is affected
    by clinical setting.
  • Dosage and form of NRT
  • Intensity of advice provided
  • Combinations

68
Results
  • 100 trials
  • Pooled odds ratio 1.71
  • Gum 1.63
  • Patches 1.73
  • Nasal Spray 2.27
  • Inhaler 2.08

69
Results
  • Tapered therapy no better than abrupt withdrawal
  • 16 hour patch equivalent to 24 hour patch
  • For Fagerstrom scores gt6, use the
  • 4 mg gum Scheduled basis?

70
Results
  • Data on combination therapy emerging.
  • Combination therapy
  • Relapsing clients with
  • Persistent craving
  • Withdrawal symptoms

71
Results
  • Odds largely independent of the intensity of
    additional support.
  • All trials provided some support.
  • Intensive support increases the likelihood of
    quitting.

72
Results
  • NRT does NOT result in increased cardiovascular
    risk.
  • NRT and smoking not associated with increased
    cardiovascular risk.
  • Harm reduction?

73
Bupropion
  • Bupropion more effective than Nicotine patch.
  • Bupropion and Patch more effective than patch
    alone.
  • Bupropion and Patch not statistically different
    than Bupropion.

74
Nicotine Replacement Therapy (NRT)
  • Nicotine replacement therapy is available in many
    different forms
  • Chewing gum (2mg and 4mg).
  • Transdermal patch (16 hour and 24 hour, varying
    doses).
  • Nasal spray.
  • Oral inhaler.
  • Sublingual tablet/lozenge.

75
Nicotine Gum
  • Nicotine ingested through the GI tract is
    extensively metabolized on first pass through the
    liver
  • Scheduled dosing (1 piece of 2mg gum/hour) and
    4mg gum for highly nicotine-dependent smokers is
    more effective
  • Nicotine absorption from gum peaks 30min after
    initiation
  • Venous nicotine levels from 2 and 4mg 1/3 and
    2/3, respectively, of the steady-state levels of
    nicotine from cigarette smoking

76
Nicotine Gum
  • Nicotine via cigarettes is absorbed directly into
    the arterial circulation
  • arterial levels from smoking are 5-10 times
    higher than those from the 2- and 4-mg gums
  • Absorption of nicotine in the buccal mucosa is
    decreased by an acidic environment
  • Patients should not use beverages (e.g., coffee,
    soda, juice) immediately before, during, or after
    nicotine gum use

77
Nicotine Gum
  • Do not chew Nicorette(R) like regular gum.
  • Begin by taking a few bites until a tingling or a
    peppery taste.
  • As soon as the tingling starts, move gum to the
    side of mouth, between gum and cheek.
  • Leave the gum there until the tingling goes away.
  • Slowly start to chew again until the tingling
    returns. Move gum to the side of your mouth
    again.
  • Keep repeating this cycle of slowly chewing, then
    moving the gum to the side of your mouth.
  • Discard after 30 minutes or when tingling ends.

78
Nicotine Patch
  • Transdermal formulations take advantage of ready
    absorption of nicotine across the skin.
  • Patches are applied daily each morning.
  • Nicotine via patches is slowly absorbed so that
    on the first day venous nicotine levels peak 6-10
    hours after administration.
  • Nicotine levels remain fairly steady with a
    decline from peak to trough of 25 to 40 with
    24-hour patches.
  • Nicotine levels are typically half those obtained
    by smoking.

79
Nicotine Patch
  • Combining the patch with other forms of NRT may
    be more effective than the patch alone and
    appears to be safe.
  • Research exists that suggests that combining
    different forms is both safe and effective.

Stapleton J. BMJ 1999318289.
80
Nicotine Patch
  • Apply one new patch at the same time of day every
    24 hours on a different skin site that is dry,
    clean, and hairless.
  • Remove backing from patch and immediately press
    onto skin. Hold for 10 seconds.
  • Wash hands after applying or removing patch.
    Throw away the patch in the enclosed disposal
    tray.
  • Wear the patch for 16 or 24 hours.

81
Nicotine Patch
  • If client craves cigarettes upon awakening, wear
    the patch for 24 hours.
  • If client has vivid dreams or other sleep
    disturbances, remove the patch at bedtime and
    apply a new one in the morning.
  • Do not cut the patch in half.

82
Nicotine Nasal Spray
  • More rapid rise in nicotine levels than gum.
  • Rise in nicotine levels produced by spray falls
    between nicotine gum and cigarettes.
  • Peak levels occur 10 minutes and venous levels
    are about 2/3 those of between-cigarette levels.

83
Nicotine Nasal Spray
  • Prime pump.
  • Blow nose. Tilt head back slightly.
  • Comfortably insert tip into nostril.
  • Breathe through mouth.
  • Spray once in each nostril-DO NOT INHALE OR SNIFF
    WHILE SPRAYING
  • Wait 2-3 minutes before blowing nose.

84
Nicotine Inhalers
  • Nicotine plugs placed inside cigarette-like rods.
  • Plugs produce a nicotine vapor when warm air is
    inspired.
  • Absorption is mostly buccal rather than
    respiratory.
  • Inhalers produce greater venous nicotine levels
    than gum but less than nasal spray.
  • Nicotine blood levels equal 1/3 that of cigarette.

85
Nicotine Inhaler
  • Inhale deeply into back of throat or puff in
    short breaths.
  • Nicotine vapor is inhaled via mouth and throat.
  • 20 minutes of active puffing exhausts nicotine.
  • Use may be continuous or intermittent.

86
Additional Therapies
  • Nicotine lozenges for buccal absorption
  • Time to first cigarette (TFC) after awakening
    useful as dose indicator
  • -- Less than 30 minutes, use 4-mg lozenge
  • -- More than 30 minutes, use 2-mg lozenge -
    Encourage use of 9 or more lozenges daily during
    first 2 to 6 weeks, with self-disciplined
    step-down use weeks 7-9, 10-12, 13-26.
  • MDD 20/day

87
Commit Lozenges
  • Recommended dosage
  • Weeks 1-6 1 lozenge every 1-2 hours.
  • Weeks 7-9 1 lozenge every 2-4 hours.
  • Weeks 10-12 1 lozenge every 4-8 hours.

88
Commit Lozenges
  • Remove lozenge from blister pack.
  • Place lozenge in mouth.
  • Allow lozenge to slowly dissolve (20-30 minutes).
    Do not chew or swallow.
  • Move lozenge from cheek to cheek.

89
Zyban (buproprion)
  • Bupropion is an effective aid to smoking
    cessation
  • There is evidence from a meta-analysis of the two
    published trials of this drug that it improves 12
    month sustained abstinence rates and reduces the
    severity of withdrawal symptoms
  • There is a very small but non-zero risk of
    serious adverse effects
  • The risk of seizures is broadly similar to other
    antidepressants at one in 1000

90
Zyban (buproprion)
  • Evidence on the effectiveness of bupropion is
    limited to medium to heavy smokers receiving
    behavioral support
  • Published trials have included smokers of 15 or
    more cigarettes per day attending frequent
    behavioral counseling sessions
  • It is not yet clear whether bupropion is more
    effective than NRT
  • One randomized placebo controlled trial has found
    a higher one year sustained abstinence rate with
    bupropion than a transdermal patch in the context
    of a behavioral support package

91
Combination Therapy
  • A Controlled Trial of Sustained-Release
    Buproprion, a Nicotine Patch, or Both for Smoking
    Cessation
  • Results
  • Abstinence rates at 12 months
  • 15.6 percent in the placebo group
  • 16.4 percent in the nicotine-patch group
  • 30.3 percent in the bupropion group (Plt0.001)
  • 35.5 percent in the group given bupropion and the
    nicotine patch Plt0.001).

92
Combination Therapy
  • By week 7, subjects in the placebo group had
    gained an average of 2.1 kg, compared to 1.6 kg
    in the nicotine-patch group, 1.7 kg in the
    bupropion group, and 1.1 kg in the
    combined-treatment group (plt0.05)
  • Weight gain at 7 weeks was significantly less in
    the combined-treatment group than in the
    bupropion group and the placebo group (plt0.05 for
    both comparisons)

93
Combination therapy
  • 311 subjects (34.8 ) discontinued one or both
    medications
  • 79 subjects stopped treatment because of adverse
    events
  • 6 in the placebo group (3.8)
  • 16 in the nicotine-patch group (6.6)
  • 29 in the bupropion group (11.9)
  • 28 in the combined-treatment group (11.4)
  • The most common adverse events were insomnia and
    headache

94
Drug Interactions
  • Amitriptyline
  • Nortriptyline
  • Imipramine
  • Clomipramine
  • Fluvoxamine
  • Trazodone
  • Fluphenazine
  • Haloperidol
  • Olanzapine
  • Clozapine
  • Chlorpromazine

95
Drug Interactions
  • Heparin
  • Theophylline
  • Tacrine
  • Insulin
  • Acetaminophen
  • Warfarin
  • Caffeine
  • Aspirin
  • Codeine
  • Lidocaine
  • Propranolol

96
Conclusions
  • Thanks
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