DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

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SECTION II
NEUROPHARMACOLOGY
Table 24–6
Nicotine Withdrawal Symptoms
Irritability, impatience, hostility
Anxiety
Dysphoric or depressed mood
Difficulty concentrating
Restlessness
Decreased heart rate
Increased appetite or weight gain
Depressed mood (dysthymic disorder, affective disorder) is
associated with nicotine dependence, but it is not known whether
depression predisposes one to begin smoking or depression develops
during the course of nicotine dependence. Depression increases significantly
during smoking withdrawal, and this is cited as one reason
for relapse.
Pharmacological Interventions. The nicotine withdrawal syndrome
can be alleviated by nicotine-replacement therapy, available with a
prescription (e.g., NICOTROL inhaler and nasal spray) or without (e.g.,
NICORETTE gum and others; COMMIT lozenges and others; and NICO-
DERM CQ transdermal patch and others). Figure 24–3 shows the blood
nicotine concentrations achieved by different methods of nicotine
delivery. Because nicotine gum and a nicotine patch do not achieve
the peak levels seen with cigarettes, they do not produce the same
magnitude of subjective effects as smoking. These methods do, however,
suppress the symptoms of nicotine withdrawal. Thus, smokers
should be able to transfer their dependence to the alternative delivery
system and gradually reduce the daily nicotine dose with minimal
symptoms. Although this results in more smokers achieving abstinence,
most resume smoking over the ensuing weeks or months.
Comparisons with placebo treatment show large benefits of nicotine
replacement at 6 weeks, but the effect diminishes with time. The nicotine
patch produces a steady blood level (Figure 24–3) and seems to
have better patient compliance than that observed with nicotine gum.
Verified abstinence rates at 12 months are reported to be in the range
of 20%. The necessary goal of complete abstinence contributes to the
poor success rate; when ex-smokers “slip” and begin smoking a little,
they usually relapse quickly to their prior level of dependence.
The search for better medications to treat nicotine addiction
has become an important goal of the pharmaceutical industry, and
other types of medication have been tested in clinical trials. A sustained-release
preparation of the antidepressant bupropion (ZYBAN;
Chapter 15), improves abstinence rates among smokers and remains
a useful option. The cannabinoid CB 1
receptor inverse agonist
rimonabant improves abstinence rates and reduces the weight gain
seen frequently in ex-smokers. Unfortunately, the CB 1
inverse agonist
mechanism led to a high frequency of depressive and neurologic
symptoms, ending its development in the U.S. Varenicline, a partial
agonist at the α 4
β 2
subtype of the nicotinic acetylcholine receptor,
improves abstinence rates but has also been linked to risk of developing
suicidal ideation. Varenicline partially stimulates nicotinic
receptors, thereby reducing craving and preventing most withdrawal
symptoms. It has high receptor affinity, thus blocking access to
nicotine, so if the treated smoker relapses, there is little reward and
Nicotine concentration (ng/ml)
20
15
10
5
0
20
15
10
5
0
20
15
10
5
Cigarettes
Chewing tobacco
0 30 60 90 120 0 30 60 90 120
Minutes
Patch
Oral snuff
Nicotine gum
0
0 4 8 12 16 20 24
Hours
ON
OFF
Figure 24–3. Nicotine concentrations in blood resulting from five
different nicotine delivery systems. Shaded areas (upper panel)
indicate the periods of exposure to nicotine. Arrows (lower panel)
indicate when the nicotine patch was put on and taken off. (From
Benowitz et al., 1988, and Srivastava et al, 1991, with permission.
Benowitz et al, 1988 Copyright © Macmillan Publishers
Ltd. Srivastava et al, 1991 Copyright © Springer Science and
Business Media.)
abstinence is more likely to be maintained. In one recent clinical
trial, the abstinence rate for varenicline at 1 year was 36.7% versus
7.9% for placebo (Williams et al., 2007).
Opioids
Opioid drugs are used primarily for the treatment of pain
(Chapter 18). Some of the CNS mechanisms that reduce
the perception of pain also produce a state of well-being
or euphoria. Thus, opioid drugs also are taken outside
medical channels for the purpose of obtaining the effects
on mood. This potential for abuse has generated much
research on separating the mechanism of analgesia from
that of euphoria in the hope of eventually developing a
potent analgesic that does not activate the brain reward