Title: Nicotine Addiction In the Psychiatrically Ill
1Nicotine Addiction In the Psychiatrically Ill
- Kumar Maharaj, R.Ph, BCPP
2Epidemiology
- 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.
3Outpatient 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.
4Smoking 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
5Overall 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.
6Nicotine 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.
7What 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).
8What 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.
9What 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.
10Dopamine Hypothesis of Schizophrenia
Hypoactivitynegativesymptoms
Hyperactivitypositivesymptoms
Adapted from Inoue and Nakata. Jpn J Pharmacol.
200186376.
11Psychopathology 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.
12Barriers 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.
13Barriers 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
14Hypotheses--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.
15HypothesesSelf-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.
16HypothesesReduction 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.
17Typicals, 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.
18Nicotine, 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.
19NonDA 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.
20Special Challenges
- Assessment
- Engagement into treatment
- Medication treatments
- Psychosocial treatments
- Program level interventions
21Special Challenges
- Assessment
- All clients must be screened at all levels of
care - The 5 As
- Ask
- Advise
- Assess
- Assist
- Arrange
22Special 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
23Special 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
24Special Challenges
- Medication treatments
- Underutilized
- Under dosed
25Special 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???
26Special Challenges
- Program level interventions
- RFA
27Somatic 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.
28Cochrane Reviews
- Objectives To determine the effectiveness of
different strategies. - Outcome Measures Abstinence from smoking after
gt 6 months.
29Aversive Therapy
- Pairs a pleasant stimulus with an unpleasant
stimulus. - InclusionRandomized trials which compared
aversion txments with inactive procedures. - Or
- Aversion txments of different intensity.
30Aversive 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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57Hypnotherapy
- Randomized trials with 6 month data.
- 9 studies.
- Hypnotherapy does not have a greater effect on 6
month quit rates than no treatment.
58Acupuncture
- 22 Studies.
- Odds ratio vs sham treatments.
- 1.5 after 6 months.
- 1.09 after 12 months.
59Silver Acetate
- 2 studies-silver acetate vs placebo.
- Odds ratio 1.05.
60Mecamylamine
- 2 small studies
- Nicotine plus mecamylamine 40
- Nicotine 20
- Mecamylamine 15
- No active drug 15
61Opioid Antagonists
- Naloxone and naltrexone.
- 2 trials-more since.
- No difference vs placebo.
62Anxiolytics
- Agents studied
- Diazepam
- Meprobamate
- Metoprolol
- Oxprenol
- Buspirone
- No evidence of efficacy
63Clonidine
- 6 trials 3 oral, 3 transdermal
- All participants received counseling
- Pooled odds ratio 1.89 vs placebo
- Prominent side effects
- Dry mouth
- Sedation
64Antidepressants
- Bupropion (5)
- Doxepin (1)
- Fluoxetine (2)
- Imipramine (1)
- Moclobemide (1)
- Nortriptyline (2)
- Selegiline (1)
- Sertraline (1)
- Tryptophan (1)
- Venlafaxine (1)
65Results
- Nortriptyline and Bupropion aid smoking cessation
- Other agents role?
66NRT
- Aim To assess the effectiveness of
- Nicotine Gum
- Transdermal patches
- Nasal Spray
- Inhalers
67NRT
- Aim To determine if NRTs efficacy is affected
by clinical setting. - Dosage and form of NRT
- Intensity of advice provided
- Combinations
68Results
- 100 trials
- Pooled odds ratio 1.71
- Gum 1.63
- Patches 1.73
- Nasal Spray 2.27
- Inhaler 2.08
69Results
- 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?
70Results
- Data on combination therapy emerging.
- Combination therapy
- Relapsing clients with
- Persistent craving
- Withdrawal symptoms
71Results
- Odds largely independent of the intensity of
additional support. - All trials provided some support.
- Intensive support increases the likelihood of
quitting.
72Results
- NRT does NOT result in increased cardiovascular
risk. - NRT and smoking not associated with increased
cardiovascular risk. - Harm reduction?
73Bupropion
- Bupropion more effective than Nicotine patch.
- Bupropion and Patch more effective than patch
alone. - Bupropion and Patch not statistically different
than Bupropion.
74Nicotine 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.
75Nicotine 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
76Nicotine 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
77Nicotine 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.
78Nicotine 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.
79Nicotine 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.
80Nicotine 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.
81Nicotine 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.
82Nicotine 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.
83Nicotine 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.
84Nicotine 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.
85Nicotine 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.
86Additional 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
87Commit 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.
88Commit 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.
89Zyban (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
90Zyban (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
91Combination 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).
92Combination 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)
93Combination 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
94Drug Interactions
- Amitriptyline
- Nortriptyline
- Imipramine
- Clomipramine
- Fluvoxamine
- Trazodone
- Fluphenazine
- Haloperidol
- Olanzapine
- Clozapine
- Chlorpromazine
95Drug Interactions
- Heparin
- Theophylline
- Tacrine
- Insulin
- Acetaminophen
- Warfarin
- Caffeine
- Aspirin
- Codeine
- Lidocaine
- Propranolol
96Conclusions