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

Deliberate abusers of high doses of benzodiazepines usually
require inpatient detoxification. Frequently, benzodiazepine abuse
is part of a combined dependence involving alcohol, opioids, and
cocaine. Detoxification can be a complex clinical pharmacological
problem requiring knowledge of the pharmacokinetics of each drug.
The patient’s history may be unreliable not simply because of lying
but also because the patient frequently does not know the true identity
or dose of drugs purchased on the street. Medication for detoxification
should not be prescribed by the “cookbook” approach but
by careful titration and patient observation. The withdrawal syndrome
from diazepam, e.g., may not become evident until the patient
develops a seizure in the second week of hospitalization. One approach
to complex detoxification is to focus on the CNS-depressant drug and
temporarily hold the opioid component constant with a low dose of
methadone. Opioid detoxification can begin later. A long-acting benzodiazepine
such as diazepam or clorazepate (TRANXENE, others) or a
long-acting barbiturate such as phenobarbital can be used to block the
sedative withdrawal symptoms. The phenobarbital dose should be
determined by a series of test doses and subsequent observations to
determine the level of tolerance. Most complex detoxifications can be
accomplished using this phenobarbital loading-dose strategy
(Robinson et al., 1981).
After detoxification, the prevention of relapse requires a longterm
outpatient rehabilitation program similar to the treatment of
alcoholism. No specific medications have been found to be useful in
the rehabilitation of sedative abusers; but, of course, specific psychiatric
disorders such as depression or schizophrenia, if present,
require appropriate medications.
Barbiturates and Older Sedatives. The use of barbiturates
and older non-benzodiazepine sedating medications
(e.g., meprobamate, glutethimide, chloral hydrate) has
declined greatly in recent years owing to the increased
safety and to the efficacy of the benzodiazepines and the
newer agents zolpidem, eszopiclone, zaleplon, and
ramelteon (Chapters 15 and 17). Abuse problems with
barbiturates resemble those seen with benzodiazepines
in many ways. Treatment of abuse and addiction should
be handled similarly to interventions for the abuse of
alcohol and benzodiazepines. Because drugs in this category
frequently are prescribed as hypnotics for patients
complaining of insomnia, physicians should be aware of
the problems that can develop when the hypnotic agent
is withdrawn. Insomnia rarely should be treated with
medication as a primary disorder except when produced
by short-term stressful situations. Insomnia often is a
symptom of an underlying chronic problem, such as
depression or respiratory dysfunction, or may be due
simply to a change in sleep requirements with age.
Prescription of sedative medications, however, can
change the physiology of sleep with subsequent tolerance
to these medication effects. When the sedative is
stopped, there is a rebound effect with worsened insomnia.
This medication-induced insomnia requires detoxification
by gradual dose reduction.
Nicotine
The basic pharmacology of nicotine and agents for smoking
cessation are discussed in Chapter 11. Because nicotine
provides the reinforcement for cigarette smoking, the
most common cause of preventable death and disease in
the U.S., it is arguably the most dangerous dependenceproducing
drug. The dependence produced by nicotine
can be extremely durable, as exemplified by the high failure
rate among smokers who try to quit. Although >80%
of smokers express a desire to quit, only 35% try to stop
each year, and fewer than 5% are successful in unaided
attempts to quit (American Psychiatric Association, 2000).
Cigarette (nicotine) addiction is influenced by multiple
variables. Nicotine itself produces reinforcement;
users compare nicotine to stimulants such as cocaine or
amphetamine, although its effects are of lower magnitude.
While there are many casual users of alcohol and
cocaine, few individuals who smoke cigarettes smoke a
small enough quantity (≤5 cigarettes per day) to avoid
dependence. Nicotine is absorbed readily through the
skin, mucous membranes, and lungs. The pulmonary
route produces discernible CNS effects in as little as
7 seconds. Thus, each puff produces some discrete reinforcement.
With 10 puffs per cigarette, the one-pack-perday
smoker reinforces the habit 200 times daily. The
timing, setting, situation, and preparation all become
associated repetitively with the effects of nicotine.
Nicotine has both stimulant and depressant actions. The
smoker feels alert, yet there is some muscle relaxation. Nicotine
activates the nucleus accumbens reward system in the brain;
increased extracellular DA has been found in this region after nicotine
injections in rats. Nicotine affects other systems as well, including
the release of endogenous opioids and glucocorticoids.
There is evidence for tolerance to the subjective effects of
nicotine. Smokers typically report that the first cigarette of the day
after a night of abstinence gives the “best” feeling. Smokers who
return to cigarettes after a period of abstinence may experience nausea
if they return immediately to their previous dose. Persons naive
to the effects of nicotine will experience nausea at low nicotine blood
levels, and smokers will experience nausea if nicotine levels are
raised above their accustomed levels.
Negative reinforcement refers to the benefits obtained from
the termination of an unpleasant state. In dependent smokers, the
urge to smoke correlates with a low blood nicotine level, as though
smoking were a means to achieve a certain nicotine level and thus
avoid withdrawal symptoms. Some smokers even awaken during the
night to have a cigarette, which ameliorates the effect of low nicotine
blood levels that could disrupt sleep. If the nicotine level is
maintained artificially by a slow intravenous infusion, the number of
cigarettes smoked and in the number of puffs decrease. Thus, smokers
may be smoking to achieve the reward of nicotine effects, to
avoid the pain of nicotine withdrawal, or most likely a combination
of the two. Nicotine withdrawal symptoms are listed in Table 24–6.
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CHAPTER 24
DRUG ADDICTION